Claims:We Claim:
1. MCT absorbate composition comprising;
MCT oil, inorganic silicate substrate and at least one excipient acceptable in nutraceutical, pharmaceutical and food industry;
which is free flowing, highly dispersible and exhibits enhanced ketogenesis effect as compared to reference formulation.

2. The composition of claim 1, comprising
65 to 85% of MCT oil,
10 to 30% of inorganic silicate substrate and
1 to 5% of at least one excipient,
by weight of the highly dispersible absorbate composition.

3. The composition of claim 2, wherein inorganic silicate substrate is selected from the group of calcium silicate, magnesium silicate, aluminium silicate, magnesium trisilicate, magnesium aluminium silicate, magnesium calcium silicate or the combination thereof.

4. The composition of claim 2, wherein at least one excipient acceptable in nutraceutical, pharmaceutical and food industry is selected from diluents, carriers, binders, disintegrants, lubricants, surfactants, glidants, solubilizers, carriers, vehicles, stabilizers, buffers, preservatives, acidifiers, alkalizers, sorbents, antioxidants, complexing agents, viscosity enhancers, plasticizers, coating materials, sweeteners, colors, flavors or the combination thereof.

5. The composition of claim 4, wherein the ratio of MCT oil to inorganic silicate substrate ranges from about 5:1 to 1:1.

6. A process for preparation of MCT absorbate composition, wherein
a. Inorganic silicate substrate is dried in suitable dryer
b. dried silicate substrate is blended with at least one excipient, which is acceptable in pharmaceutical, nutraceutical and food industry
c. blend of silicate and the excipient is granulated with MCT oil

7. Process as claimed in claim 6, wherein inorganic silicate substrate is selected from the group of calcium silicate, magnesium silicate, aluminium silicate, magnesium trisilicate, magnesium aluminium silicate, magnesium calcium silicate or the combination thereof.

8. Process as claimed in claim 6, wherein at least one excipient acceptable in nutraceutical, pharmaceutical and food industry is selected from diluents, carriers, binders, disintegrants, lubricants, surfactants, glidants, solubilizers, carriers, vehicles, stabilizers, buffers, preservatives, acidifiers, alkalizers, sorbents, antioxidants, complexing agents, viscosity enhancers, plasticizers, coating materials, sweeteners, colors, flavors or the combination thereof.

9. Process as claimed in claim 8, wherein
a. Inorganic silicate substrate, such as calcium silicate is dried in suitable dryer
b. dried calcium silicate substrate is blended with at least one excipient, selected from disintegrant, surfactant or the combination thereof
c. blend of calcium silicate and the excipients is granulated with MCT oil to get free flowing highly dispersible composition

10. Process as claimed in claim 6, wherein blend of silicate substrate and at least one excipient is granulated with MCT oil by employing rapid mixer granulator, high shear granulator, high shear mixer coupled with a sprayer, fluidized bed granulator, extrusion spheronizer, spray granulator or the combination thereof.

Dated this 24th February 2020

Dr. Rupali Suvarnapathaki
Deputy General Manager,
Intellectual Property Rights (Nutraceuticals),
Inventia Healthcare Limited
, Description:Field of the Invention:
The invention relates to compositions comprising absorbate of medium chain triglyceride (MCT) oil. The absorbate may be comprised of MCT oil, inorganic silicate substrate and at least one excipient which is acceptable in nutraceutical, food and pharmaceutical industry. MCT absorbate composition is granular and free flowing, and may exhibit high dispersibility in water, milk and other beverages, even during aging of the composition, over the period of shelf life. More preferably MCT absorbate as described herein, is comprised of calcium silicate and at least one more excipient. The composition comprising absorbate of MCT and inorganic silicate substrate entraps MCT oil effectively and does not allow it to come to the surface of granules, thus avoiding rancidity over the period of shelf life of the composition. The invention also relates to a process for preparation of highly dispersible composition; wherein MCT oil is absorbed on silicate substrate in presence of at least one more excipient to get free flowing granules. The MCT absorbate composition, as described herein is stable and exhibits enhanced ketone body generation as compared to reference formulation. The composition can be prepared by simple process using easily available industrial equipment to prepare free flowing granules which can be formulated in desired dosage form and conveniently administered to the subjects.

Background:
Medium-chain triglyceride (MCT) oil contains medium-length chains of fats called triglycerides. Triglycerides have two main purposes; they are either burned for energy or stored as body fat. Triglycerides are named after their chemical structure, specifically the length of their fatty acid chains. All triglycerides consist of a glycerol molecule and three fatty acids. Due to their shorter length, MCTs are easily digested and many health benefits are linked to the way human body processes these fats. They are metabolized differently than the long-chain triglycerides (LCT) found in most other foods.

MCTs are generally made by processing coconut and palm kernel oils in the laboratory. It is most commonly extracted from coconut oil, as more than 50% of the fat in coconut oil comes from MCTs. These fats are also found in many other foods, such as dairy products. The medium-chain fatty acids in MCTs have 6–12 carbon atoms. Four main different types of medium-chain fatty acids exist-C6: caproic acid or hexanoic acid, C8: caprylic acid or octanoic acid, C10: capric acid or decanoic acid and C12: lauric acid or dodecanoic acid. Out of these fatty acids, of caprylic and capric acid are most commonly used for MCT oil, which have specific unique benefits.
Interest in medium-chain triglycerides (MCTs) has grown rapidly over the last few years. Many advocates boast that MCT oil can aid weight loss. In addition, it has become a popular supplement among athletes and bodybuilders. Athletes sometimes use it for nutritional support during training, to increase exercise performance, for decreasing body fat and increasing lean muscle mass, and for weight loss. MCTs are used along with usual medications for treating food absorption disorders including diarrhoea, steatorrhea (fat indigestion), celiac disease, liver disease, and digestion problems due to partial surgical removal of the stomach (gastrectomy) or the intestine (short bowel syndrome). MCTs are sometimes also used as a source of fat in total parenteral nutrition (TPN). Intravenous MCT oil is also given to prevent muscle breakdown in critically ill patients. These are a fat source for patients who cannot tolerate other types of fats. Researchers also think that these fats produce ketone bodies in the body that might help fight Alzheimer's disease. These fats might also result in weight loss because the body uses them in a different way to other types of fats. Due to their shorter chain length, medium-chain triglycerides are more rapidly broken down and absorbed into the body. This makes them a quick energy source and less likely to be stored as fat. There are many other health benefits related to MCT oil, which make it very best for the health, including keto generation and the energy for sports activities.

Use of MCT oil in the ketogenic diet is becoming very popular recently. A ketogenic diet involves limiting carbohydrates to increase the levels of circulating ketones. The reduction in carbohydrates signals the liver to produce ketones from fats. This process alters the energy metabolism from a typical carbohydrate to glucose system to a fat to ketone system. The ability for the body to run on either energy source is one that has allowed us to survive throughout the ages on many different food sources. However, most of the people can’t tolerate the multiple tablespoons of traditional MCT oil required to stimulate meaningful amounts of ketones. Stomach upset and diarrhoea are the likely result. Only C-8 MCT oil supports an abundance of ketones with a dosage free of gastric side effects. With the lower dosage comes a lower calorie content and more effective stimulation of the fat to ketone energy cycle. C-8 MCT oil supports the production of ketones which can be used by the brain as an alternative energy source. As C-8 MCT’s produce ketones and do not get stored as body fat, weight management and rapid energy production are additional benefits.

Although MCT oil is useful for variety of health applications, it is difficult to administer it to the subjects in its natural oily form, owing to its oily nature and inconvenience with respect to administration of accurate dose. Moreover, oily form of MCT is not acceptable by the subjects all the time. Therefore, formulators have tried ways to convert it into solid dosage form, for ease of administration and acceptability by the consumers. Most of the products currently available in the market are in the powder form, but these experience the problem of dispersibility over the period of time, during shelf life of the product. In such cases, as the product ages, the product cannot be dispersed in water, milk, coffee or other beverages, thus affecting the application of the product and use by the consumers.
Many prior art references describe efforts made to formulate MCT into solid dosage forms using matrix of gums, fibres, proteins or maltodextrins through the process of emulsification and spray drying method to get powder formulations.
Patent application KR1701326 describes a powder composition of medium chain triglyceride oil and natural tocopherol, and its method of preparation. The composition comprises of natural tocopherol, emulsifier and maltodextrins or dextrin. The process involves mixing pre-heated medium chain triglyceride, with natural tocopherol, emulsifier and maltodextrin or dextrin. The mixture is sterilised and pulverised at high temperature followed by homogenization of the mixture, and the powder composition is obtained by spray drying the homogenate.
Patent application CN 104054849 relates to high-fat-content medium-chain triglyceride powder for food or food additive which comprises glucose syrup, modified starch, and the excipient. The process of preparation involves heating MCT oil at temperature range of 600 to 900 C and mixing all the oil soluble component in MCT oil and similarly mixing all the water soluble component in the water phase followed by adding the oil phase gradually in water phase and adjusting the pH to 6. The temperature of the emulsion is maintained, and the emulsion is further homogenised, and spray dried to obtain High-fat-content medium-chain triglyceride.
PCT application WO2007070701 describes a method of preventing cognitive impairment, progressive decline in cognitive function and related changes in brain of mammals by administering MCT in their diet regime. The MCT oil was mixed in the basic diet supplement for administration to the mammals. This treatment by MCT oil increases circulating concentration of at least one type of ketone bodies, which provide an alternative energy source to supplement the energy deficit in neuronal cells of Alzheimer’s patients.
US patent 10111849 relates to a method of treating or preventing Alzheimer’ disease, or other loss of cognitive function caused by reduced neuronal metabolism, by orally or intravenously administering an effective amount of medium chain triglycerides to the patient. Neobee 895 (caprylic triglyceride) was used as a source for MCT which was blended with whipping cream and given to patients. No other formulation efforts are mentioned in the patent, but it mainly aims at proving use of MCT in Alzheimer’s disease.
Although powder formulations of MCT prepared by emulsification and spray drying method are described in the prior art, it is observed that they exhibit poor flow property. Also, the dispersibility property of many of these marketed products gets hampered over the storage time, as the product undergoes aging. This problem of poor dispersibility affects the application of product in the form of beverage; wherein it is required to be dispersed easily in water, milk or any other suitable vehicle before consumption. Poorly flowing non-granular product poses problem during formulation into suitable dosage forms or while handling the product for filling in sachets. Further, the marketed MCT formulations also suffer from the problem of rancidity as MCT oil has tendency to come to the surface of the formulation over the period of time, thus affecting the palatability of the product. Thus there is a need of developing MCT formulation, using alternate excipients and process, which will exhibit good flow property and retain its high dispersibility properties and desired sensory attributes, even during aging of the product over shelf-life.
The inventors of the present invention have come up with simple and industrially applicable process for preparation of granular, free flowing and highly dispersible MCT formulation. Inventors also make use of alternate excipients, such as combination of inorganic silicate substrate and at least one more excipient, which are obtained from natural sources and are useful and safe for human consumption. None of the prior art reports free flowing and highly dispersible MCT absorbate composition which is prepared using inorganic silicate substrate. MCT absorbate compositions can be dispersed effectively and easily in water, milk and other beverages over the shelf life of the product. The composition does not exhibit presence of surface oil or rancidity during storage of the product, thus ensuring effective entrapment of MCT oil on inorganic silicate substrate. Free flowing and high dispersible MCT absorbate compositions are thus useful for consumption in different forms for enhancing ketogenesis.
Objectives:
Main objective of the present invention is to provide free flowing and highly dispersible compositions comprising absorbate of medium chain triglyceride oil.

One more objective of this invention is to provide the absorbate composition comprising MCT, inorganic substrate and at least one excipient which is acceptable in nutraceutical, food and pharmaceutical industry.

One important objective of the present invention is to provide a composition comprising silicate as inorganic substrate, on which MCT oil is absorbed to result into an absorbate.

Still one more objective of the present invention is to provide highly dispersible absorbate composition comprising 65 to 85% of MCT oil, 10 to 30% of inorganic silicate substrate and 1 to 5% of at least one excipient by weight of the composition.

One important objective of the present invention is to provide MCT absorbate composition which exhibit dispersibility property, during entire shelf life of the product, thus useful for various applications wherein the products needs to be dispersed in liquid vehicle.

Further one objective of the present invention is to provide MCT absorbate composition comprising inorganic substrate selected from calcium silicate, magnesium silicate, aluminium silicate, magnesium trisilicate, magnesium aluminium silicate, magnesium calcium silicate and the combinations thereof.

One objective of this invention is to provide highly dispersible composition comprising MCT absorbate which is comprised of excipient selected from diluents, carriers, binders, disintegrants, lubricants, glidants, solubilizers, carriers, vehicles, stabilizers, buffers, preservatives, acidifiers, alkalizers, sorbents, antioxidants, complexing agents, viscosity enhancers, plasticizers, coating materials, sweeteners, colors, and flavors.

One important objective of the present invention is to provide the composition comprising MCT absorbate which is free flowing and granular in nature.

Still one more objective of the present invention is to provide absorbates comprising MCT and inorganic silicate substrate which exhibits high dispersibility in water, milk and other beverages.

One more objective of the present invention is to provide absorbate composition which effectively entraps MCT oil using inorganic silicate substrate, thus avoiding presence of surface oil on the composition and does not result into rancidity over shelf-life or storage of the product.

One more objective of the invention is to provide a process for preparation wherein MCT oil is absorbed on inorganic silicate in presence of at least one excipient by process of spray granulation. The absorbate composition is stable and exhibits enhanced ketone body generation as compared to reference formulation.

The composition can be prepared using simple process and easily available industrial equipment to prepare the dosage form which can be conveniently administered to the subjects.

Detailed Description:
Figure 1 illustrates the dispersibility test for Example 1, Figure 2 illustrates the dispersibility test for Example 4 and Figure 3 illustrates the dispersibility test of Example 5.

The invention relates to highly dispersible compositions comprising absorbates of medium chain triglyceride (MCT) oil, comprising inorganic silicate substrate and at least one excipient which is acceptable in nutraceutical, food and pharmaceutical industry. The composition is free flowing, granular and stable and exhibits high dispersibility in water, milk and other beverages The composition maintains its dispersibility property during entire shelf life, thus making it useful to the consumers for various applications. The composition effectively entraps MCT oil to avoid presence of any surface oil on the granules or development of rancidity over its storage time. MCT absorbate composition exhibits enhanced generation of keto bodies as compared to the reference formulation.

As used herein, the term ‘highly dispersible composition’ means the composition which gets rapidly or easily dispersed throughout the vehicle through disintegration and conversion of granules to small particles, thus effecting rapid mixing of the composition with the vehicle. The composition may get dispersed on its own, after adding the composition in the vehicle or slight stirring may be required at times to facilitate the distribution of the particles throughout the vehicle. Highly dispersible composition thus gets distributed rapidly, resulting into homogenization of the composition with vehicle, such as water, milk, tea, coffee and other beverages. Moreover, the composition retains its dispersibility property even after aging, over entire shelf life recommended for the product. Highly dispersible composition in reference of the present invention is MCT absorbate composition, which is in the form of free-flowing granules. The composition is comprised of MCT oil, inorganic silicate substrate and at least one more excipient, which is acceptable in pharmaceutical, food or nutraceutical industry.

As used in the present context, the term ‘absorbate’ means the complex formed by phenomenon of absorption between the active (here medium chain triglyceride -MCT) and the substrate, wherein the substrate acts as an absorbent. MCT enters the pores and gets absorbed in porous substrate or absorbent, which is inorganic silicate in the present invention. MCT oil is thus absorbed in sufficient amount of inorganic silicate substrate, preferably calcium silicate, to get absorbate of MCT. The absorbate is also comprised of one more excipient, which may be mixed with the substrate, before subjecting to MCT.

As described herein, the term ‘inorganic substrate’ means the component of the absorbate which is porous in nature and used to absorb MCT oil based on its oil absorption property. The inorganic substrate, as used herein, belongs to silicate class of compounds, mainly selected from, but not limited to calcium silicate, magnesium silicate, aluminium silicate, magnesium trisilicate, magnesium aluminium silicate, magnesium silicate and the mixtures thereof. Preferable compound used according to present invention is calcium silicate which has high oil absorption capacity in its pores. The inorganic substrate is also called as absorbent because of its absorption property. This substrate absorbs MCT and forms the absorbate, which is granular and highly dispersible in nature.

‘MCT absorbate’ as described herein, is comprised of MCT oil, inorganic silicate substrate and at least one more excipient. The absorbate is free flowing, granular composition which is highly dispersible in water, tea, coffee and other beverages. Thus it can be formulated in suitable dosage forms for convenient administration to the subjects as per requirement.

The term “medium-chain triglyceride (MCTs)” refers to esters of medium-chain fatty acids, having a structure with an ester bond between a medium-chain fatty acid and glycerine.
Medium chain triglycerides consist of a mixture of triglycerides of saturated fatty acids, mainly of caprylic acid and capric acid. Examples of the medium-chain fatty acid include lauric acid, caprylic acid, capric acid, caproic acid, heptylic acid, and pelargonic acid.
Since medium-chain triglycerides are present in vegetables such as coconut and palm fruit and dairy products such as cow milk, medium-chain fatty acids and esters extracted (including rough extraction) or purified or roughly purified therefrom can be used in the present invention. In some cases, products obtained by a chemical synthesis method and commercially available products may be used as a part or the whole of the medium-chain triglycerides.

As per one embodiment of the invention, MCT oil (medium chain triglyceride) appears as a clear oily liquid and may be comprised of fatty acids of varying carbon chain length, ranging from C6, C8, C10 and C12 in different percentage content. Preferably, MCT oil may be comprised of combination of C8 and C10 fatty acids in varying ratio. It may also contain C8 fatty acids in major amount and remaining being other fatty acid content.
According to one more embodiment of the invention, MCT oil may be composed of 50 to 80% of C8 and 20 to 50% of C10 fatty acids, along with not more than 2% of C6, not more than 3% of C12 and not more than 1% of C14 fatty acids.
As per one embodiments of the invention, MCT oil may be composed of 55 to 65% of C8 and 35 to 45% of C10 fatty acids. MCT oil may be also composed of 95 to 98% of C8 fatty acids caprylic acids, remaining composition mainly being comprised of C10 fatty acids.

As per one embodiment of this invention, the absorbate composition may be comprised of 65 to 85% of MCT oil by weight of the composition. More preferably, the composition may be comprised of 70 to 80% of MCT oil by weight of the composition.

According to one important embodiment of the invention, inorganic substrate as described herein may be selected from silicate compounds from the group of, but not limited to calcium silicate, magnesium silicate, aluminium silicate, magnesium trisilicate, magnesium aluminium silicate, magnesium silicate and the mixtures thereof. These silicate compounds are safe for human and animal administration and therefore acceptable in pharmaceutical, nutraceutical and food industry. The substrate may be also called as absorbent, because of its oil absorption property in present context. As herein described, more preferably calcium silicate or its precipitated form is used as substrate or absorbent.
Calcium silicate is the chemical compound, also known as calcium orthosilicate and is sometimes formulated as 2CaO·SiO2. It is also referred to by the trade name Zeopharm 600, which is a precipitated form of calcium silicate, having high absorptive property. Calcium silicate is a white free-flowing amorphous powder with high porosity. It can be derived from naturally occurring limestone and diatomaceous earth, a siliceous sedimentary rock. It is one of a group of compounds that can be produced by reacting calcium oxide and silica in various ratios. It has a low bulk density and exhibits good oil absorption property.
According to one embodiment of the invention, the absorbate composition may be comprised of 10 to 30% of calcium silicate by weight of the composition. More preferably, the composition may be comprised of about 15 to 25% of calcium silicate.

The composition according to the current invention may further comprise additional excipients known in the art, which are acceptable to pharmaceutical, nutraceutical and food industry. The term "acceptable in pharmaceutical, nutraceutical and food industry" excipient, refer to those compounds and materials which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio. In some embodiments, the term “acceptable in pharmaceutical, nutraceutical and food industry " can also mean approved by a regulatory agency of the Federal or a state government or listed in the appropriate or other generally recognized Pharmacopoeia for use in animals, and more particularly, consumption in humans.
The excipient, as described herein may be selected from the group of, but not limited to diluents, carriers, binders, disintegrants, lubricants, glidants, solubilizers, carriers, vehicles, stabilizers, buffers, preservatives, acidifiers, alkalizers, sorbents, antioxidants, complexing agents, viscosity enhancers, plasticizers, coating materials, sweeteners, colours, flavours or the combination thereof. The excipient, as used herein in suitable concentration may enhance the properties of the composition such as dispersibility, stability, flowability and the like.

The compositions may be comprised of at least one excipient selected from the group 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.
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.
According to one more embodiment, the disintegrants may be selected from sodium starch glycolate, crospovidone, croscarmellose sodium, croscarmellose calcium, croscarmellose potassium, sodium carbonate, sodium hydrogen carbonate, microcrystalline cellulose (MCC), calcium carbonate, starch, starch 1500, modified starch, pregelatinized starch, crosslinked carboxymethyl starch, sodium hydrogen carbonate, hydroxypropyl cellulose, sodium carboxymethylcellulose or mixtures thereof.
The disintegrant may be used in concentrations from 1% to 5% by weight of the composition. More preferably, the disintegrant used in the present invention may be selected from croscarmellose sodium and microcrystalline cellulose in appropriate percentage.
The surfactant may be, selected from the group of, but not limited to, hydrophilic surfactants, lipophilic surfactants, mixtures thereof. The surfactants may be anionic, nonionic, cationic, zwitterionic or amphiphilic. Preferably, the surfactant may be PEG-20-glyceryl stearate {Capmul® by Abitec), PEG-40 hydrogenated castor oil (Cremophor RH 40® by BASF), PEG 6 corn oil (Labrafil® by Gattefosse), lauryl macrogol - 32 glyceride {Gelucire 44/U® by Gattefosse), stearoyl macrogol glyceride (Gelucire 50/13® by Gattefosse), polyglyceryl - 10 mono dioleate (Caprol ® PEG 860 by Abitec), propylene glycol oleate (Lutrol OP® by BASF), propylene glycol dioctanoate (Captex® by Abitec), propylene glycol caprylate/caprate (Labrafac® by Gattefosse), glyceryl monooleate (Peceol® by Gattefosse), glycerol monolinoleate (Maisine ® by Gattefosse), glycerol monostearate (Capmul® by Abitec}, PEG- 20 sorbitan monolaurate {Tween 20® by Id), PEG - 4 lauryl ether (Brij 30® by Id), sucrose distearate (Sucroester 7® by Gattefosse), sucrose monopalmitate (Sucroester 15® by Gattefosse), polyoxyethylene-polyoxypropylene block copolymer (Lutrol® series BASF), polyethylene glycol 660 hydroxystearate, (Solutol® by BASF), sodium lauryl sulphate, sodium dodecyl sulphate, dioctyl suphosuccinate, L- hydroxypropyl cellulose, hydroxylethylcellulose, hydroxy propylcellulose, propylene glycol alginate, sodium taurocholate, sodium glycocholate, sodium deoxycholate, betains, polyethylene glycol (Carbowax® by DOW), d-a- tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS® by Eastman), or mixtures thereof.
The lubricants, glidants, solubilizers may be selected from list of suitable excipients known in the art.

As per one important embodiment of this invention, the absorbate composition effectively entraps MCT oil by using inorganic silicate substrate, thus avoiding presence of surface oil as well as rancidity of the composition.
If MCT oil is not entrapped effectively in inorganic silicate substrate, then there are chances of its presence on surface of the composition, which is called as surface oil. This surface oil may result into rancidity of the composition, in the form of disagreeable smell, texture and appearance. Rancidity further results into marked increase in the acid value of fats and oils. Acid value is tested through peroxide value determination, which gives idea about generation of oxidative by products of the compound. Thus peroxide value is indicative of rancidity of the composition, which can be calculated in the form of miliequivalents of oxygen per kilogram of the product.

As per one embodiment of the invention, the invention also relates to a process for preparation of highly dispersible MCT composition. As per this process, inorganic silicate substrate is dried well in suitable dryer equipment. Silicate substrate is then blended with the excipient selected from disintegrants such as microcrystalline cellulose, croscarmellose sodium or the mixture thereof. The blend is granulated using MCT oil. The granules may be re-sized to get final free flowing granular composition.
As per one more embodiment of this invention, inorganic silicate substrate used in the process may be selected from the group of, but not limited to, calcium silicate, magnesium silicate, aluminium silicate, magnesium trisilicate, magnesium aluminium silicate, magnesium silicate and the mixtures thereof. These silicates are used as excipients in pharmaceutical, nutraceutical as well as food industry and perform various functions, based on their concentrations employed in the formulation. As per important embodiment of this invention, more preferably calcium silicate is used as substrate for MCT oil to prepare absorbate composition.

As per one embodiment of the present invention, suitable and commonly known processes and equipment as employed in the industry may be used for drying of silicate substrate, such as sun drying, tray drying, vacuum drying, microwave drying, or using tunnel dryers, roller or drum dryers, fluidized bed dryers, spray dryer, pneumatic dryers, rotary dryers, trough dryers, bin dryers, belt dryers, freeze dryers and the like and the combinations thereof.

According to one more embodiment, dried silicate substrate is mixed with at least one more excipient, preferably from the class of disintegrants, selected from but not limited to sodium starch glycolate, crospovidone, croscarmellose sodium, croscarmellose calcium, croscarmellose potassium, sodium carbonate, sodium hydrogen carbonate, microcrystalline cellulose, calcium carbonate, starch and derivatives such as modified starch, pregelatinized starch, crosslinked carboxymethyl starch, sodium hydrogen carbonate, hydroxypropyl cellulose, sodium carboxymethylcellulose or mixtures thereof.
According to one more embodiment, dried silicate substrate is mixed with at least one more excipient, preferably from the class of surfactant, selected from the group of, but not limited to, PEG-20-glyceryl stearate {Capmul® by Abitec), PEG-40 hydrogenated castor oil (Cremophor RH 40® by BASF), PEG 6 corn oil (Labrafil® by Gattefosse), lauryl macrogol - 32 glyceride {Gelucire 44/U® by Gattefosse), stearoyl macrogol glyceride (Gelucire 50/13® by Gattefosse), polyglyceryl - 10 mono dioleate (Caprol ® PEG 860 by Abitec), propylene glycol oleate (Lutrol OP® by BASF), propylene glycol dioctanoate (Captex® by Abitec), propylene glycol caprylate/caprate (Labrafac® by Gattefosse), glyceryl monooleate (Peceol® by Gattefosse), glycerol monolinoleate (Maisine ® by Gattefosse), glycerol monostearate (Capmul® by Abitec}, PEG- 20 sorbitan monolaurate {Tween 20® by Id), PEG - 4 lauryl ether (Brij 30® by Id), sucrose distearate (Sucroester 7® by Gattefosse), sucrose monopalmitate (Sucroester 15® by Gattefosse), polyoxyethylene-polyoxypropylene block copolymer (Lutrol® series BASF), polyethylene glycol 660 hydroxystearate, (Solutol® by BASF), sodium lauryl sulphate, sodium dodecyl sulphate, dioctyl sulphosuccinate, L- hydroxypropyl cellulose, hydroxylethylcellulose, hydroxy propylcellulose, propylene glycol alginate, sodium taurocholate, sodium glycocholate, sodium deoxycholate, betains, polyethylene glycol (Carbowax® by DOW), d-a- tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS® by Eastman), or mixtures thereof.
As per the process of this invention, calcium silicate and the excipient can be mixed in suitable equipment which are used for solid material blending such as blender, ribbon mixer, rapid mixer granulator, ribbon blender, vertical blender, powder mixer, mixer machine, double cone blender, paddle mixer, high intensity mixers and mills and the like; or the combination of dryers can be employed to achieve dried substrate.

As per one embodiment of this invention the blend of calcium silicate and the excipients is granulated by absorbing MCT oil in the mixture. The mixture can be sieved to get free flowing granular composition. Suitable equipment, which is commonly known to the person skilled in the art can be used for granulation process, such as rapid mixer granulator, high shear granulator, high shear mixer coupled with a sprayer, fluidized bed granulator, extrusion spheronizer and the like.
The granules are free flowing and exhibit high dispersibility. These granules can further be used as such for adding in water, milk, tea, coffee or other beverages or can be formulated in suitable dosage form such as tablets and capsules as required by the consumers. Some of the compositions may have good flow but may not exhibit dispersibility property. The compositions may exhibit high dispersibility and can be suitable for beverage applications. The granular compositions which exhibit good flow properties can be used for filling in sachets, compressing in tablets or filling in capsules or any other suitable dosage form as per the customer requirement.

The MCT absorbate composition, as described herein is evaluated for stability and dispersibility. The composition is also checked for presence of surface oil and peroxide value, to confirm about effective entrapment of MCT oil in inorganic calcium silicate and absence of rancidity over storage time of the product. The granular absorbate composition is also tested in animal experimental model for ketogenesis effect and compared with the reference marketed formulation.
The composition can be prepared using simple process and easily available industrial equipment to get highly dispersible free flowing granules which can be formulated in desired dosage form and conveniently administered to the subjects.

The invention is now illustrated with non – limiting examples.

Example 1
Calcium silicate (20.2%) was dried in tray dryer until loss on drying was obtained below 3%. Calcium silicate was sifted through #40 sieve. MCT oil (79.79%, obtained from palm source, having C8:C10 content in ratio of 60:40) was weighed and heated to 70°C. Calcium silicate was transferred to the mixing bowl and MCT oil was sprayed on it while continuously stirring the mass. Final product -MCT absorbate was resized through #18 sieve.

Example 2
Calcium silicate (21.53%) was dried in tray dryer until loss on drying below 3% was obtained. Calcium silicate was sifted through #40 sieve. MCT oil (78.46%, obtained from coconut source, having C8:C10 content in ratio of 60:40) was weighed and heated to 70°C. Calcium silicate was transferred to the mixing bowl and MCT oil was sprayed on it, while continuously stirring the resulting blend throughout the process.
Final product -MCT absorbate was resized through #18 sieve.

Example 3
Calcium silicate (20.67%) was dried in tray dryer until LOD below 3% was obtained. Calcium silicate and microcrystalline cellulose (4.8%), were sifted through #40 sieve. MCT oil (73.07%, obtained from coconut source, having C8 content 96.8%) and polysorbate 80 (1.44%) were weighed and heated to 70°C. Calcium silicate was transferred to the bowl and MCT was sprayed on blend while the materials in the bowl were stirred continuously throughout the process. The product was resized through #18 sieve to get MCT absorbate composition.

Example 4
Calcium silicate (23.39%) was dried in tray dryer until loss on drying below 3% was obtained. Calcium silicate was sifted through #40 sieve. MCT oil (75.49%, obtained from coconut source, having C8 content 99%) and polysorbate (1.10%) were weighed and heated to 70°C and stirred continuously throughout the process. Calcium silicate was transferred to the mixing bowl and MCT oil was sprayed on blend in the bowl. Final product -MCT absorbate was resized through #18 sieve.

Example 5
Calcium silicate (20.67%) was dried in tray dryer until LOD below 3% was obtained. Calcium silicate and microcrystalline sodium (4.8%) were sifted through #40 sieve. MCT oil (73.07%) and polysorbate 80 (1.44%) was weighed and heated to about 70°C and stirred continuously throughout the process. Calcium silicate was transferred to mixing bowl. Microcrystalline cellulose was added to calcium silicate in the bowl to ensure uniform mixing. Oil was sprayed on blend in the bowl while stirring continuously throughout the process. The product was passed through #18 sieve to get granular MCT absorbate composition.

Example 6
Calcium silicate (19.6%) was dried in tray dryer until LOD below 3% was obtained. Calcium silicate, microcrystalline cellulose (3.92%), and croscarmellose sodium (1.47%) were sifted through #40 sieve. MCT oil (73.52%) and polysorbate 80 (1.47%) was weighed and heated to about 70°C and stirred continuously throughout the process. Calcium silicate was transferred to mixing bowl. Microcrystalline cellulose and croscarmellose sodium were added to calcium silicate in the bowl to ensure uniform mixing. Oil was absorbed on blend in the bowl and materials in the bowl were stirred continuously throughout the process. Final product was passed through #18 sieve to get granular MCT absorbate composition.

Example 7: Stability study of MCT absorbate composition of Example 1, 4 and 5
Three reproducible batches of granular composition packed in HDPE (High density polyethylene) drum container were subjected to stability study at 40°C/75% and % assay was checked at the end of 1, 2 and 3 months.

Table 1: Stability data for MCT composition of Example 1
Batch No. Initial 40°C/ 75% RH
1 month 3 months 6 months
Batch 1 79.06 78.2 77.27 78.72
Batch 2 79.3 80.56 78.77 78.1
Batch 3 80.25 79.3 80.07 78.47

Table 2: Stability data for MCT composition of Example 4
Batch No. Initial 40°C/ 75% RH
1 month 3 months 6 months
Batch 1 75.21 78.73 76.95 73.76
Batch 2 75.83 77.59 77.76 73.46
Batch 3 75.56 79.16 78.12 73.52

Table 3: Stability data for MCT composition of Example 5
Batch No. Initial 40°C/ 75% RH
1 month 2 months 3 months
Batch 1 71.82 71.6 70.26 70.62
Batch 2 71.26 71.94 71.53 70.65
Batch 3 72.37 71.57 71.98 71.31

The composition was found stable over a period of 3 months with respect to assay content of MCT.

Example 8: Dispersibility of MCT absorbate composition
Dispersibility of MCT composition (Example 1, 4 and 5) was checked in the vehicle. Specific weighed amount of the composition was added in fixed volume of water and stirred briefly with a spoon. The observations are recorded in the following table and the outcome can be also seen in the photographs (Figure 1, 2 and 3).

Table 4: Dispersibility test for MCT absorbate compositions

Sample Time taken for complete dispersion Visual observation
Example 1 -- The composition didn’t disperse in the vehicle, it only floated on the surface, even after stirring
Example 4 -- The composition didn’t disperse in the vehicle, it only floated on the surface, even after stirring
Example 5 5 sec The composition immediately dispersed in the vehicle after stirring, to result into uniform dispersion

It was observed that composition comprising MCT and calcium silicate (Example 1) does not disperse in water, even after stirring. The composition comprising MCT, calcium silicate and polysorbate (Example 4), only became turbid after adding in the vehicle, but didn’t disperse completely. But the composition of Example 5- comprising MCT, calcium silicate, polysorbate and microcrystalline cellulose, disperses immediately after adding in the liquid vehicle.
These compositions can be useful for applications such as beverages, wherein high dispersibility helps to disperse the composition in vehicle of interest such as water, milk, tea, fruit juices and other suitable vehicles as per the requirement of the consumer.
MCT absorbate compositions of the invention are granular and free flowing. Therefore, the examples which do not show dispersibility, for its application in beverages, can be very well used for filling in sachets, for compression into tablets, filling in capsules or formulating in any other suitable forms, because of their granular nature and free flowing property.

Example 9: Effective entrapment of MCT oil in calcium silicate substrate in absorbate composition
Entrapment of MCT oil in calcium silicate substrate is checked through surface oil determination and test for rancidity of the composition.

A. Surface Oil Determination
Procedure: Weighed amount of MCT absorbate powder composition is spread on butter paper. The paper is folded to absorb oil from powdered composition. The paper is rinsed using 10-12 ml of methanolic NaOH solution, which is further refluxed with water condenser for 10min. Then 15 ml of methanolic solution of Boron Trifluoride is added to the system, followed by addition of 4ml of n-Heptane. The solution is cooled to attain room temperature and 15 ml of saturated NaCl solution is added. Anhydrous sodium sulphate is added to organic layer to absorb excess of water and organic layer is injected in GC- FID, using DB wax column with Helium as the carrier gas. The injection volume is 1µl with the injector temp at 220°C and detector temp at 260°C.The column oven temperature is controlled between 70°C to 240°C at the rate of 5°C/min.
MCT oil is also tested as control; while marketed sample was used as reference material in this study. MCT absorbate composition of Example 7 was kept on stability at 40°C/ 75% RH conditions and the surface oil determination was carried out for initial as well as stability sample after 6 months.

Table 5: Surface oil determination
Sample Surface oil content (% w/w)
MCT Oil Control 102.81
Composition of Example 5 Test sample-Initial 0.16
Stability study
Composition of Example 5 40°C/ 75% RH (6 months) 0.15
Composition of Example 5 40°C/ 75% RH (6 months) 0.17
Composition of Example 5 40°C/ 75% RH (6 months) 0.18

This study indicates that MCT absorbate composition of the invention is substantially free of surface oil in initial as well as stability samples. There was no significant difference in surface oil content of test as well as reference formulation. Surface oil was substantially same as initial value, even after exposing the formulation at high humid and temperature and therefore it could be concluded that the effectively entrapped/ absorbed oil did not leach out from the absorbate during stability studies.

B. Peroxide Value Determination
Process: Blank solution was prepared by taking 30 mL of chloroform: acetic acid (3:2) in 250mL conical flask. 0.5mL saturated potassium iodide solution was added to it. 30mL purified water was added and shaken well. 4-5 drops of 1% starch indicator was added to the system and titrated against 0.01N sodium thiosulphate using endpoint from blue to colourless (reading B).
Sample was prepared by weighing accurately about 5g of sample and adding 30mL of chloroform: acetic acid (3:2). 0.5mL saturated potassium iodide solution was added to it. 30ml purified water was added and shaken well. 4-5 drops of 1% starch indicator was added to the system and titrated against 0.01N sodium thiosulphate using endpoint from blue to colourless (Reading -S).
Peroxide value
Peroxide value (milliequivalent of O2 per kg of sample) = (S-B) × N × 1000
W

Table 6: Rancidity Value determination
Rancidity study [Peroxide Value (meq of oxygen per kg of sample)]
MCT Oil Control 1.62
MCT composition Example 7 Initial 1.31
Stability study
MCT composition Example 7 40°C/ 75% RH (6 months) 1.54
MCT composition Example 7 40°C/ 75% RH (6 months) 1.28
MCT composition Example 7 40°C/ 75% RH (6 months) 1.29

This study indicates that there was no increment of peroxide value in the formulation while exposing the formulation at high humid (changes for hydrolytic rancidity), high temperature (thermo-catalytic). The formulation does not contain antioxidant to prevent oxidative rancidity. Therefore, it could be concluded that the effectively entrapped/ absorbed oil did not leach out from the absorbate during stability studies.

Example 10: Effect of Medium chain triglycerides (MCT) supplementation on ketogenesis in rats

Study Design: The effect of medium chain triglyceride (MCT) supplementation on ketogenesis was evaluated in a 4-week study conducted in Rats.
The animals in the Control group (Group 1) were administered sunflower oil as a source of long chain triglycerides (LCT). Animals in Groups 2 and 3 were administered the reference and test MCT respectively at a dose of 2 g/Kg body weight for a period of 4 weeks, based on the clinically effective dose.

Reference formulation was a marketed formulation which was available in the form of MCT powder comprised of MCT oil and gum acacia, which is prepared by emulsification and spray drying method. Test formulation is the MCT absorbate composition of the present invention.

Ketogenic effect of the test and reference MCT was evaluated by assessing the levels of ketone bodies viz. Acetoacetate and ß-Hydroxybutyrate in blood and brain tissue at the end of the treatment period.

Result and Discussion:
After 4 weeks of MCT administration, significant elevation in plasma acetoacetate and ß-Hydroxybutyrate was observed in the animals treated with the Test MCT.

• Acetoacetate and ß-Hydroxybutyrate levels in Plasma: Once daily oral administration of test MCT at a dose of 2 g/kg significantly increased the plasma acetoacetate levels (p<0.0001) compared to the sunflower oil treated vehicle control group.
It was found that oral supplementation of the Test MCT resulted in a three-fold increase in blood acetoacetate levels over the Control group.
• Treatment with the Test MCT resulted in significantly higher levels of acetoacetate in plasma compared to the Reference MCT group.
• Treatment with the Test MCT also resulted in a significant elevation in plasma ß-Hydroxybutyrate levels (p<0.0001 compared to the vehicle control) which is superior to the effect of reference MCT. Plasma ß-Hydroxybutyrate levels observed in the test MCT group were two-fold higher than the reference MCT group.

• Acetoacetate and ß Hydroxybutyrate levels in brain tissue: Treatment with test MCT resulted in a significant increase in the brain ß-Hydroxybutyrate levels (p<0.0001) compared to the sunflower oil treated control group. Treatment with the reference MCT showed a significant increase (p<0.001) in brain ß-Hydroxybutyrate levels compared to vehicle treated animals. No changes were observed with respect to acetoacetate levels in brain samples compared to the vehicle treated animals. Analysis of ketone bodies in brain tissue of animals treated with the test MCT revealed a 5-fold elevation in ß-Hydroxybutyrate levels compared to the Control group. The increase in brain ß Hydroxybutyrate levels as a result of MCT supplementation was nearly similar in the Test and Reference MCT groups. No significant elevation was seen in acetoacetate levels in brain tissues as a result of MCT administration.

• Effect on body weight:
Once daily oral administration of test and reference MCT at the doses specified did not result in any significant changes in body weight in the animals. There was no change in the pattern of body weight gain between the MCT treated animals and the LCT treated animals. No adverse clinical signs observed during the course of treatment.

Conclusion: The levels of acetoacetate in blood were higher in the Test MCT group compared to the Reference MCT group. Similarly, there was a two-fold increase in plasma ß-Hydroxybutyrate levels over the Reference MCT group. The increase in plasma ketone bodies seen in the Test MCT group was statistically significant compared to the Reference MCT group. The results indicate that the Test MCT had a superior effect on ketogenesis compared to the Reference MCT.