A nutraceutical composition for managing reproductive health in women

Abstract

A synergistic nutraceutical composition comprising one or more inositol, macronutrients, micronutrients, an antioxidant, and nutraceutically acceptable excipients. The resulting composition is suitable for oral administration as a nutraceutical formulation for the management of the symptoms associated with Polycystic Ovary Syndrome (PCOS) and used as a substitute for at least one meal of the day.

Description

[0001] FIELD OF THE INVENTION

[0002] The present application relates to a nutraceutical composition for use in alleviating the symptoms associated with Polycystic Ovary Syndrome (PCOS) or Polycystic Ovarian Disease (PCOD) and also aiding the weight management.

[0003] BACKGROUND OF THE INVENTION

[0004] Polycystic Ovary Syndrome (PCOS) is a multifactorial disorder affecting women of reproductive age and is characterized by the presence of multiple cysts in the ovaries containing immature follicles. The condition commonly presents with menstrual abnormalities such as irregular menstrual cycles, hyperinsulinemia, hyperandrogenism, enlarged ovaries, and the formation of multiple abnormal cysts. Women with PCOS may also experience symptoms including hirsutism (excess facial and body hair growth), acne, obesity, and darkening of the skin. In addition to reproductive complications, PCOS is associated with metabolic and endocrine disturbances that increase the risk of developing conditions such as Type 2 Diabetes, hypertension, dyslipidaemia, and cardiovascular diseases. Furthermore, women with PCOS often experience psychological complications, including mood disorders such as depression and anxiety, which further contribute to the complexity of the disorder.

[0005] Inositol is a naturally occurring carbocyclic sugar abundantly present in human tissues and plays a critical role in cell signal transduction involving hormones, neurotransmitters, and growth factors. Chemically, inositol is a six-carbon polyol with the same molecular formula as glucose and exists in nine stereoisomeric forms, including Myo-inositol and D-chiro-inositol. These molecules are incorporated into cell membranes as phosphatidyl-myo-inositol, which serves as a precursor for Inositol trisphosphate, a second messenger involved in the action of several hormones including insulin and Follicle-stimulating hormone. In the body, myoinositol promotes estrogen production, whereas D-chiro-inositol contributes to androgen synthesis, and the enzyme epimerase stimulated by insulin converts myo-inositol to D-chiro-inositol to maintain physiological balance. However, in women with PCOS, insulin resistance often leads to compensatory hyperinsulinemia, which disrupts this balance and contributes to hyperandrogenism. Elevated androgen levels impair follicular development and disturb the normal ratio between FSH and Luteinizing hormone, thereby preventing the selection of a dominant follicle and adversely affecting oocyte maturation, which may ultimately result in infertility.US11918018B2 discloses nutraceutical compositions and methods for the dietary management of PCOS. The compositions include ingredients that reduce hyperandrogenism and improve insulin sensitivity, such as Inositol, Monacolin K, and Curcumin. The document further describes oral administration of these ingredients, optionally under physician monitoring, and their formulation into a single over-the-counter nutraceutical supplement intended to improve menstrual cyclicity, reduce symptoms of PCOS, and support fertility. Case studies are also presented demonstrating benefits such as improvement of symptoms and successful conception in women with prior infertility.

[0006] EP3081097B1 discloses discloses a pharmaceutical composition or supplement intended for the treatment and management of metabolic disorders associated with Insulin resistance, including conditions such as Diabetes mellitus, PCOS, Hepatic steatosis, Cirrhosis, Hyperlipidaemia, Atherosclerosis, and Obesity.

[0007] IN202441017823A discloses an ocular gel formulation containing liposomal encapsulated Dorzolamide hydrochloride for the treatment of Glaucoma. The invention focuses on improving drug delivery to the eye by enhancing the bioavailability of dorzolamide hydrochloride and increasing the reduction of Intraocular pressure.

[0008] The above-mentioned documents do not disclose any well-defined and optimized composition that comprehensively targets the underlying hormonal and metabolic imbalances associated with PCOS, such as Insulin resistance and Hyperandrogenism.

[0009] Therefore, there is a need to develop an improved composition capable of effectively addressing the complex metabolic and hormonal disturbances associated with PCOS.

[0010] OBJECT OF THE INVENTION

[0011] An object of the present invention is to provide a nutraceutical composition for the management of the symptoms associated with Polycystic Ovary Syndrome (PCOS).

[0012] SUMMARY OF THE INVENTION

[0013] The present invention provides a nutraceutical composition for the management of the symptoms associated with Polycystic Ovary Syndrome (PCOS).

[0014] An oral nutraceutical composition comprising:(a) one or more inositols;

[0015] (b) macronutrients;

[0016] (c) micronutrients;

[0017] (d) an antioxidant; and

[0018] (e) nutraceutically acceptable excipients.

[0019] The inositols are selected from group consisting of scyllo-inositol, muco-inositol, myo-inositol, neo-inositol, D-chiro-inositol, preferably myo-inositol, neo-inositol, D-chiro-inositol, more preferably myo-inositol and D-chiro-inositol. The inositols are present in the range of 1 g to 35 g per 100 g, preferably from 1 g to 25 g per 100 g, more preferably from 1 g to 20 g per 100 g of the composition. The macronutrients are selected from group consisting of carbohydrates, proteins, fats, and fibers.

[0020] The nutraceutical composition of the present application comprises the carbohydrates selected from group consisting of cereals like rice, wheat, millet, maize, sorghum, and components like glucose, sucrose, sorbitol, xylitol, maltitol, trehalose, maltodextrin, processed starch, amylose starch, tapioca starch, fructose, lactose, gums or combinations thereof, more preferably skimmed milk powder and gums or combinations thereof. The carbohydrates are present in the range of 20 g to 70 g per 100 g, preferably 25 g to 65 g per 100 g, more preferably 30 g to 60 g per 100 g of the composition.

[0021] The nutraceutical composition of the present application comprises proteins selected from group consisting of concentrates, isolates and hydrolysates of one or more of casein, caseinates (including sodium, calcium, potassium caseinates), whey protein ,milk protein , skimmed milk, soy protein, pea protein, canola protein, wheat and fractionated wheat proteins, corn and its fractions including zein, rice, oat, potato, peanut, green pea powder, green bean powder or combinations thereof, more preferably skimmed milk powder, soybean flour, defatted soybean flour, soy protein isolate, gram flour, ragi flour or combinations thereof.

[0022] The proteins are present in the range of 5 g to 65 g per 100 g, preferably 10 g to 55 g per 100 g, more preferably 15 g to 45 g per 100 g of the composition.

[0023] The nutraceutical composition of the present application comprises lipids / fats selected from group consisting of soy based ingredients, nuts, oilseeds, vegetable oils or combinations thereof, preferably, olive oil, hazelnut oil, palm oil, sunflower oil, high oleic sunflower oil,safflower oil, soybean oil, coconut oil, sesame oil, pumpkin seed oil, peanut oil, mustard oil, linseed oil, com oil, rice bran oil or and the like or combinations thereof, more preferably, high oleic sunflower oil powder, soya fat powder or combinations thereof. The fats are present in the range of 1 g to 45 g per 100 g, preferably 3 g to 30 g per 100 g, more preferably 5 g to 20 g per 100 g of the composition. The fibers are selected from group consisting of soluble fiber, prebiotic fiber, functional fiber, resistant starch, insoluble fiber, preferably soluble fiber, prebiotic fiber, functional fiber, more preferably prebiotic fiber. The fibers are in the range of 1g to 30 g per 100 g preferably 1 g to 20 g per 100 g more preferably 1 g to 15 g per 100 g of the composition.

[0024] The micronutrients are selected from group consisting of vitamins, minerals or combinations thereof. The vitamins are selected from group consisting of vitamin E, vitamin A, vitamin Bl, vitamin B6, vitamin B 12, vitamin C, vitamin D2, preferably vitamin E, vitamin A, vitamin B6, vitamin D2, more preferably vitamin E, vitamin B6, vitamin D2. The vitamins are present in the range of 2 mg to 25 mg per 100g, preferably 4 mg to 20 mg per 100g, more preferably 6 mg to 15 mg per 100g of the composition.

[0025] The antioxidant is selected from group consisting of alpha-lipoic acid (ALA), vitamin C, vitamin E, lipoic acid, beta-carotene, and carotenoids or combinations thereof. The antioxidant component is alpha-lipoic acid (ALA). ALA is in the range of 100 mg to 1200 mg per 100g, preferably 150 mg to 1100 mg per 100g, more preferably 200 mg to 1000 mg per 100g of the composition. The alpha-lipoic acid (ALA) is encapsulated with encapsulating agent(s) consisting of chitosan, cyclodextrin, alginic acid, soy phosphatidylcholine, egg lecithin, cholesterol, Tween 20, Tween 60, Tween 80, polyethylene oxide, gelatin, HPMC, calcium caseinate, sodium alginate, silicon dioxide, povidone or combinations thereof. The encapsulating agent consists of alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin or combinations thereof. The encapsulating agent is gamma-cyclodextrin.

[0026] Alpha lipoic acid is encapsulated with gamma-cyclodextrin wherein the alpha-lipoic acid and gamma-cyclodextrin are present in the ratio of 1:1 to 1:6. The alpha-lipoic acid (ALA) is encapsulated with cyclodextrin by a process comprising spray drying and wet granulation. The inositols and macronutrients are present in the ratio of 1:10 to 1:25. The inositols and micronutrients are present in the ratio 1 :0.01 to 1 : 0.5. The inositols and antioxidant are presentin the ratio of 1 :0.1 to 1 :5. The composition can be used as a substitute for at least one meal of a day.

[0027] BRIEF DESCRIPTION OF FIGURES

[0028] Figures la, lb, and 1c depict coating uniformity analysis of Specimen 6 using Raman spectroscopy.

[0029] Figures 2a and 2b depict coating uniformity analysis of Specimen 12 using Raman spectroscopy.

[0030] Figure 3 depicts TGA graph for pure ALA (i.e. non-coated ALA), Specimen 12 and gammacyclodextrin.

[0031] Figure 4 depicts the graph showing mean change in blood glucose concentration after consuming ‘Test food A’, in comparison with ‘Reference food’; over a period of 2 hours. Figure 5 depicts the graph showing mean change in blood glucose concentration after consuming ‘Test food B’ in comparison with ‘Reference food’; over a period of 2 hours.

[0032] DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0033] The present invention provides a nutraceutical composition for the management of the symptoms associated with Polycystic Ovary Syndrome (PCOS).

[0034] An oral nutraceutical composition comprising:

[0035] (a) one or more inositols;

[0036] (b) macronutrients;

[0037] (c) micronutrients;

[0038] (d) an antioxidant; and

[0039] (e) nutraceutically acceptable excipients.

[0040] The inositols are selected from group consisting of scyllo-inositol, muco-inositol, myo-inositol, neo-inositol, D-chiro-inositol, preferably myo-inositol, neo-inositol, D-chiro-inositol, more preferably myo-inositol and D-chiro-inositol. The inositols are present in the range of 1 g to 35 g per 100 g, preferably from 1 g to 25 g per 100 g, and more preferably from 1 g to 20 g per 100 g of the composition. The macronutrients are selected from group consisting of carbohydrates, proteins, fats, and fibers.

[0041] The nutraceutical composition of the present application comprises the carbohydrates selected from group consisting of cereals like rice, wheat, millet, maize, sorghum, and components like glucose, sucrose, sorbitol, xylitol, maltitol, trehalose, maltodextrin, processed starch, amylosestarch, tapioca starch, fructose, lactose, gums or combinations thereof, more preferably skimmed milk powder and gums or combinations thereof. The carbohydrates are present in the range of 20 g to 70 g per 100 g preferably 25 g to 65 g per 100 g more preferably 30 g to 60 g per 100 g of the composition.

[0042] The nutraceutical composition of the present application comprises proteins selected from group consisting of concentrates, isolates and hydrolysates of one or more of casein, caseinates (including sodium, calcium, potassium caseinates), whey protein ,milk protein , skimmed milk, soy protein, pea protein, canola protein, wheat and fractionated wheat proteins, corn and its fractions including zein, rice, oat, potato, peanut, green pea powder, green bean powder or combinations thereof, more preferably skimmed milk powder, soybean flour, defatted soybean flour, soy protein isolate, gram flour, ragi flour or combinations thereof.

[0043] The proteins are present in the range of 5 g to 65 g per 100 g preferably 10 g to 55 g per 100 g more preferably 15 g to 45 g per 100 g of the composition.

[0044] The nutraceutical composition of the present application comprises lipids / fats selected from group consisting of soy based ingredients, nuts, oilseeds, vegetable oils or combinations thereof, preferably, olive oil, hazelnut oil, palm oil, sunflower oil, high oleic sunflower oil, safflower oil, soybean oil, coconut oil, sesame oil, pumpkin seed oil, peanut oil, mustard oil, linseed oil, com oil, rice bran oil or and the like or combinations thereof, more preferably, high oleic sunflower oil powder, soya fat powder or combinations thereof. The fats are present in the range of 1 g to 45 g per 100 g preferably 3 g to 30 g per 100 g more preferably 5 g to 20 g per 100 g of the composition. The fibers are selected from group consisting of soluble fiber, prebiotic fiber, functional fiber, resistant starch, insoluble fiber, preferably soluble fiber, prebiotic fiber, functional fiber, more preferably prebiotic fiber. The fibers are in the range of 1g to 30 g per 100 g preferably 1 g to 20 g per 100 g more preferably 1 g to 15 g per 100 g of the composition.

[0045] The micronutrients are selected from group consisting of vitamins, minerals or combinations thereof. The vitamins are selected from group consisting of vitamin E, vitamin A, vitamin Bl, vitamin B6, vitamin B 12, vitamin C, vitamin D2, preferably vitamin E, vitamin A, vitamin B6, vitamin D2, more preferably vitamin E, vitamin B6, vitamin D2. The vitamins are present inthe range of 2 mg to 25 mg per 100g, preferably 4 mg to 20 mg per 100g, more preferably 6 mg to 15 mg per 100g of the composition.

[0046] The antioxidant is selected from group consisting of alpha-lipoic acid (ALA), vitamin C, vitamin E, lipoic acid, beta-carotene, and carotenoids or combinations thereof. The antioxidant component is alpha-lipoic acid (ALA). ALA is in the range of 100 mg to 1200 mg per 100g preferably 150 mg to 1100 mg per 100g, more preferably 200 mg to 1000 mg per 100g of the composition. The alpha-lipoic acid (ALA) is encapsulated with encapsulating agent(s) consisting of chitosan, cyclodextrin, alginic acid, soy phosphatidylcholine, egg lecithin, cholesterol, Tween 20, Tween 60, Tween 80, polyethylene oxide, gelatin, HPMC, calcium caseinate, sodium alginate, silicon dioxide, povidone or combinations thereof. The encapsulating agent consists of alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin or combinations thereof. The encapsulating agent is gamma-cyclodextrin.

[0047] Alpha lipoic acid is encapsulated with gamma-cyclodextrin wherein the alpha-lipoic acid and gamma-cyclodextrin are present in the ratio of 1:1 to 1:6. The alpha-lipoic acid (ALA) is encapsulated with cyclodextrin by a process comprising spray drying and wet granulation. The inositols and macronutrients are present in the ratio of 1:10 to 1:25. The inositols and micronutrients are present in the ratio 1 :0.01 to 1 : 0.5. The inositols and antioxidant are present in the ratio of 1 :0.1 to 1 :5. The composition can be used as a substitute for at least one meal of a day.

[0048] TECHNICAL ADVANTAGES

[0049] • The synergistic composition of the present invention has its unique properties of the ingredients which assist in the efficiency of the composition,

[0050] • The said nutraceutical composition has GI between 10 to 40.

[0051] • The said nutraceutical composition upon administration to a subject, for a treatment period in the range of 1 to 5 months, preferably 2 to 4 months, more preferably3 months, reduces the levels of at least one androgen-associated outcomes, selected from, the levels of total testosterone (TT), androstenedione (AND), and dehydroepiandrosterone sulfate (DHEA-S).

[0052] • The shelflife of the said nutraceutical composition is in the range of 3 years, preferably 2 years, more preferably 1 year.• The said nutraceutical composition upon administration to a subject, for a treatment period in the range of 1 to 5 months, preferably 2 to 4 months, more preferably 3 months, reduces the levels of total testosterone in the subject by at least about 2% as compared to the levels of total testosterone before the treatment period.

[0053] • The said nutraceutical composition upon administration to a subject, for a treatment period in the range of 1 to 5 months, preferably 2 to 4 months, more preferably3 months, reduces the levels of at least one glucose metabolism outcomes, selected from fasting insulin level (FINS), fasting blood glucose level (FBG), homeostatic model assessment of insulin resistance (HOMA-IR) and HbAlc.

[0054] • The said nutraceutical composition provides a total energy content of 300 kcal to 500 kcal per 100 g of the composition.

[0055] • The said nutraceutical composition is stable for a time period in the range of 0.5 year to 3 years, preferably 1 year to 2 years, more preferably 1 year, when subjected to stability studies at conditions selected from one or more of 30 °C ±2 °C / 65%RH± 5% and 40 °C ± 2 °C / 75% RH ± 5%.

[0056] • The said nutraceutical composition retains at least 90% amount of alpha-lipoic acid, when it is subjected to stability studies for a time period in the range of range of 0.5 year to 3 years, preferably 1 year to 2 years, more preferably 1 year at 40 °C ± 2 °C / 75%RH± 5%.

[0057] EXAMPLES

[0058] EXAMPLE 1: PROCESS OF ENCAPSULATION OF ALA COMPRISING WET GRANULATION.

[0059] Process of encapsulation or coating of ALA with cyclodextrin comprises steps of:

[0060] a) Weighing and dispensing ALA and cyclodextrin in different quantities as mentioned in the table below:

[0061] Table 1: Quantities of ALA and cyclodextrin used in encapsulation of ALA comprising wet granulation;

[0062]

[0063] b) passing ALA and cyclodextrin through suitable sieve and dry blending between 5 to 30 minutes;

[0064] c) adding distilled water to the dry blend of ALA and cyclodextrin in an amount between 5% w / w to 40% w / w with continuous mixing to make homogeneous wet mass;

[0065] d) transferring complex wet mass to hot air oven with the oven temperature maintained between 40°C to 90°C to achieve the moisture content of between 5% to 20%;

[0066] e) dried coated ALA is again sifted through suitable sieve and dry blended for 20 minutes to 40 minutes to obtain a homogenous blend.

[0067] EXAMPLE 2: PROCESS OF ENCAPSULATION OF ALA COMPRISING SPRAY DRYING.

[0068] Process of encapsulation or coating of ALA with cyclodextrin using spray drying; comprises steps of:

[0069] a) Weighing and dispensing ALA and cyclodextrin in different quantities as mentioned in the table below:

[0070] Table 2: Quantities of ALA and cyclodextrin used in encapsulation of ALA comprising spray drying

[0071]

[0072]

[0073] j) preparing aqueous solution of alkaline pH between 10 to 14;

[0074] c) adding required quantities of ALA and cyclodextrin to the solution prepared in step (b) and mixing for 5 to 20 minutes;

[0075] d) lowering the pH of the solution between 4 to 7 by adding suitable acid in required quantity;

[0076] e) examining the solution visually in order to determine the suitability of the specimen for spray drying;

[0077] f) homogenizing the solution and subjecting it to spray drying wherein inlet temperature is in the range of 150°C to 200°C and outlet temperature is in the range of 50°C to 100°C to achieve the moisture content of between 1% to 10%.

[0078] EXAMPLE 3: EXPERIMENTAL DETAILS: EVALUATION OF COATED ALA SAMPLES;

[0079] To study the effects of the different encapsulation materials, and subsequent efficacy of the encapsulation process a series of trials were conducted.

[0080] Specimens from Example 1 and Example 2 were evaluated to analyze homogeneity of coating. I. Visual analysis of specimens:

[0081] Specimens from Example 1 (Specimen 2, Specimen 4 and Specimen 6) and from Example 2 (Specimen 8, Specimen 10, Specimen 12) were visually analysed. Results of the analysis are summarized in the tables below.

[0082] Table 3: Visual analysis of Specimens from Example 1

[0083]

[0084]

[0085] Table 4: Visual analysis of Specimens from Example 2 Specimen 8, Specimen 10, Specimen 12 were visually analysed at two steps.

[0086]

[0087]

[0088] Conclusion: It was concluded that gamma-cyclodextrin can encapsulate highest amount of alpha-lipoic acid and can make a stable complex. Hence, Specimen 6 and Specimen 12 were chosen for further evaluations.

[0089] II. Evaluation of coating uniformity of specimens:

[0090] Specimen 6 and Specimen 12 were subjected to Raman spectroscopy. Results of the analysis are summarized in the table below.

[0091] Table 5: Coating uniformity analysis of Specimen 6 and Specimen 12 using Raman spectroscopy

[0092]

[0093] Figures la, lb and 1c:

[0094] Figures la, lb and 1c depict coating uniformity analysis of Specimen 6 (ALA coated with gamma-cyclodextrin using wet granulation process) using Raman spectroscopy.

[0095] Raman spectra of Specimen 6 shows three distinct regions compared to reference spectra of ALA and gamma-cyclodextrin from the library. This indicates that the wet granulation process does not provide uniform coating. (Please refer to the Raman Spectra in Figure la, Figure lb and Figure 1c).Figure la depicts the comparison of a ‘spectrum of the region of Specimen 6 represented by horizontal lines’ with the ‘reference spectrum of ALA’, indicating presence of ALA in that region.

[0096] Figure lb depicts comparison of a ‘spectrum of the region of Specimen 6 represented by light grey colour’ with the ‘reference spectrum of gamma-cyclodextrin’, indicating presence of gamma-cyclodextrin in that region.

[0097] Figure 1c depicts comparison of a ‘spectrum of the region of Specimen 6 represented by black colour’ with the ‘reference spectra of both ALA and gamma-cyclodextrin’ indicating presence of both the components in that region.

[0098] Since both the components- ALA and gamma-cyclodextrin-were individually identified in the Specimen 6, with no trace of the other component at that point, it was concluded that the coating was NOT homogenous throughout the sample.

[0099] Figures 2a and 2b:

[0100] Figures 2a and 2b depict coating uniformity analysis of Specimen 12(ALA coated with gammacyclodextrin using spray drying process) using Raman spectroscopy.

[0101] Raman spectra of Specimen 12 shows single region compared to reference spectra of gammacyclodextrin from the library, (e refer Figure 2a).

[0102] Figure 2a depicts comparison of a ‘spectrum of Specimen 12’ with the ‘reference spectrum of gamma-cyclodextrin’, indicating presence of gamma-cyclodextrin. In Figure 2a, along with peak at -478 cm'1(marker of gamma-cyclodextrin), a slight shoulder is seen at -510 cm'1(marker of ALA). Hence, it can be seen that the Specimen 12 gives a homogenous spectral signature of gamma-cyclodextrin throughout the imaged area.

[0103] Figure 2b depicts comparison of a ‘spectrum of Specimen 12’ with the ‘reference spectrum of

[0104] Hence, it was observed that no region of the sample was found to contain signature for pure ALA or pure gamma-cyclodextrin.

[0105] Hence, it was concluded that the coating was homogenous throughout the sample.

[0106] Conclusion: The results show that ALA coated with gamma-cyclodextrin using a process comprising spray drying, was uniformly coated. Hence, it was concluded that the process of encapsulation of ALA comprising spray drying has higher encapsulation efficiency.

[0107] III. Analysis of thermal stability of coated ALA:

[0108] Specimen 12 and sample of non-coated ALA were further subjected to Thermogravimetric analysis (TGA) for analysing the efficiency of the coating achieved. Results of the analysis are summarized in the table below.Table 6: Analysis of thermal stability of Specimen 12 and sample of non-coated ALA using TGA

[0109]

[0110] The TGA graph in Figure 3 clearly indicates that the thermal stability of ALA is increased after encapsulation of ALA with gamma cyclodextrin using spray drying technique.

[0111] Conclusion: In terms of thermal stability, Specimen 12 was found to be more stable than noncoated ALA.

[0112] IV. Stability of coated ALA at 50°C and 40°C

[0113] Specimen 12 and sample of non-coated ALA were subjected to high temperatures 50°C and 40°C for a period of about one month and assay was performed to check thermal stability of both the samples. Results of the thermal stability of coated ALA (Specimen 12) and non-coated ALA at 50°C and 40°C are given in the table below.

[0114] Table 7: Thermal stability of Specimen 12 and sample of non-coated ALA

[0115]

[0116] Conclusion: It was observed that coated ALA can retain more than 95% of ALA content when subjected to high temperatures of 50°C and 40°C whereas non-coated ALA retains about 53% of ALA and about 80% ALA when subjected to 50°C and 40°C respectively. Hence it was concluded that coated ALA has better thermal stability than non-coated ALA.

[0117] EXAMPLE 4: COMPOSITIONS COMPRISING INOSITOLS, MACRONUTRIENTS, MICRONUTRIENTS, AND ANTIOXIDANTS.

[0118] Table 8: Exemplary compositions comprising inositols, macronutrients, micronutrients, and antioxidants of Formulation 1 to Formulation 7 (Fl to F7).

[0119]

[0120] Process of manufacturing for the compositions of formulation 1 to formulation 7, comprises of following steps:

[0121] Step I: Sift all the powdered ingredients including coated ALA and non-coated ALA through appropriate sieve;

[0122] Step II: Prepare a blend of essential micronutrients and excipients;

[0123] Step III: Prepare a blend of necessary macronutrients, inositols and ALA;

[0124] Step IV : Dry blend all the blends mentioned in steps II, and III;

[0125] Step V : Pack the powder composition prepared in the Step IV in a suitable container (flavour wise).

[0126] EXAMPLE 5: EVALUATION OF COMPOSITIONS COMPRISING MACRONUTRIENTS, MICRONUTRIENTS, INOSITOLS AND ANTIOXIDANTS.

[0127] I. Evaluation of organoleptic parameters and flow properties:

[0128] Formulation 3 and Formulation 6 were subjected to organoleptic evaluation and other quality control tests for powders. Results of said organoleptic evaluation are summarized in the table below:Table 9: Evaluation of Formulation 3 and Formulation 6

[0129]

[0130] The flow properties of the composition are assessed using Hausner ratio and Carr’s index and such other tests. The flow properties are of the composition are categorized as follows:

[0131]

[0132] Conclusion: Formulation 3 has better palatability.

[0133] II. Microbiological evaluation of compositions:

[0134] Formulation 3 and formulation 6 were subjected to microbiological evaluation. Results of microbiological evaluation are summarized in table below:

[0135] Table 10: Microbiological evaluation of Formulation 3 and formulation 6

[0136]

[0137] Conclusion: Synergistic Nutraceutical compositions of present applications comply with the specifications in terms of microbial evaluation.

[0138]

[0139] Composition of Formulation 3 was subjected to in-vivo clinical studies, wherein glucose used as a reference standard. The aim of the clinical study was to evaluate GI of the composition.

[0140] Study design and methodology:

[0141] The Formulation 3 from two different batches (as described in the table below) were subjected to the clinical study. Interventions for the study were as follows:

[0142] Table 11: Interventions for the clinical study

[0143]

[0144] Assessment of Glycemic index (GI):

[0145] The GI is defined as the incremental area under the blood glucose elicited by 25 g of available carbohydrate containing test food portion expressed as a percentage of the response of reference drink that is 25 g of glucose (27.5 g of glucose monohydrate) consumed by the same participant.

[0146] The GI of each test meal i.e. ‘Test Food A’ and ‘Test Food B’ was determined in normal healthy subjects (n=15) with age >18 to <45 and with BMI > 18.5 to < 22.9 kg / m2. All participants consumed a reference food- glucose drink (25 g available carbohydrate; 27.5 g glucose monohydrate) on three separate occasions and two test foods-Test food A and Test food B on two separate days in random order.

[0147] Participants who were not familiar with blood sampling via finger-pricking (capillary blood sampling) performed a practice test to acquaint them with the procedure and to control the effects of anxiety on blood glucose response. All the participants underwent 3 days of reference food testing and 2 days for test food in random order with 2-3 days washout between measurements to minimize carry over effects. Participants visited the GI testing Centre each test day in the morning after a 10-12 hr overnight fast.

[0148] For assessment of GI, fasting blood samples were taken twice within 5 minutes and average is recorded as 0 min by finger-prick, using an automatic lancet device before consumption of the food and the baseline value taken as a mean of these two values. The participants then consumed either 25g available carbohydrate portion of the test foods: Test food A and Test food B on separate occasions. The first bite / sip in the mouth is set as time 0 and the first bloodsample is taken conventionally at exactly 15 mins afterwards and further capillary blood samples were obtained at 30, 45, 60, 90 and 120 minutes after the start of the test food. Participants were given with a 125ml of water during the subsequent 2h for GI testing.

[0149] GI value of the test food (%) = Blood glucose IAUC value for the test food X 100

[0150] IAUC value of the Reference Food

[0151] Figure 4 depicts the graph showing mean change in blood glucose concentration after consuming ‘Test food A’, in comparison with ‘Reference food’; over a period of 2 hours. Figure 5 depicts the graph showing mean change in blood glucose concentration after consuming ‘Test food B’ in comparison with ‘Reference food’; over a period of 2 hours.

[0152] Measurement of IAUC and calculation of GI for Test food A and Test food B is shown in the table below.

[0153] Table 12: Individual Mean IAUC of ‘Reference food’ and ‘Test food A’ ‘Test food B’, GI of the ‘Test food A’ GI of the ‘Test food B’

[0154]

[0155]

[0156] SEM*: Standard Error of Mean, ** Dropout, ***Mean plus 2SD.

[0157] (**Dropout=The GI study included fifteen participants with a normal BMI, out of which 2 participants dropped out due to personal reasons. Further 1 participant for Test food A dropped out and 1 participant with GI value greater than mean plus 2SD were removed as an outlier for Test food A. Thus, the GI was declared based on 11 participants for Test food A and 13 participants for Test food B.)

[0158] Result of the clinical study: Results of the clinical study is summarized in the table below.

[0159] Table 13: Glycemic Indices of all the test foods assessed

[0160]

[0161] Conclusion: Both the test foods were found to be in the low GI category.

[0162]

[0163] Formulation 3 was subjected to an open label, interventional, multicenter, non-randomized, single arm, proof of concept study to evaluate the impact of nutraceutical composition for a treatment period of at least at 3 months (i.e., at least 3-months of consumption of the nutraceutical composition) as compared to baseline.

[0164] It was observed that the formulation 3 was found to lower the levels of total testosterone (TT), androstenedione (AND), dehydroepiandrosterone sulfate (DHEA-S), fasting insulin, fasting glucose, HOMA-IR and HbAlc when it is administered to the subjects with PCOS symptoms / condition. The composition of the present application administered as a meal replacement (at least one meal a day).

[0165] EXAMPLE 8: STABILITY STUDY:

[0166] ‘Formulation 3 (Batch-1)’ and ‘Formulation 3 (Batch-2)’ were subjected to real time stability studies and accelerated stability studies. Results of stability studies are summarized in the tables below. Procedures for all the assays were followed as given in the different standard literature sources like IP, ISO, AO AC etc.5 Table 14: Results of real time stability study (30°C ± 2°C / 65% RH ± 5%) for composition

[0167] of Formulation 3 (Batch- 1)

[0168]

[0169] Table 15: Results of real time stability study (30 °C ± 2 °C / 65% RH± 5%) for composition of Formulation 3 (Batch-2)

[0170]

[0171]

[0172] Table 16: Results of accelerated stability study (40°C ± 2°C / 75% RH ± 5%) for composition of Formulation 3 (Batch- 1)

[0173]

[0174]

[0175] Table 17: Results of accelerated stability study (40°C ± 2°C / 75% RH ± 5%) for composition of Formulation 3 (Batch-2)

[0176]

[0177] Result of the stability studies:

[0178] There is no significant change observed in nutrients level and nutrients delivery was within the specification during the stability period.Conclusion Both the compositions- ‘Formulation 3 (Batch- 1)’ and ‘Formulation 3 (Batch-2)’ were found to be stable at accelerated condition for 6 months and long term condition up to 12 months.

[0179] Results of the clinical studies described by above mentioned figures and tables indicate that both the compositions- ‘Formulation 3 (Batch-1)’ and ‘Formulation 3 (Batch-2)’ fall in Tow-GF category. This underscores the ability of the composition to reduce the risk of diabetes associated with PCOS. Also, the ability of the compositions to provide about 50 % to 80% less calories than the regular Indian meal highlights its capacity to aid in weight management without compromising with the requirements of daily intake of essential nutrients.

[0180] Therefore, the overall assessment and data points signal towards the potential of the composition of the present application, in managing reproductive health in women. In a nutshell, composition of the present application helps in alleviating the symptoms associated with PCOS and simultaneously provides comprehensive nutrition to the body to restore and maintain the hormonal balance.

[0181] The above description clearly mentions that the composition of the present invention is a synergistic composition showing unexpected properties by the interaction of its ingredients.

Claims

We Claim:

1. An oral nutraceutical composition comprising:(a) one or more inositols;(b) macronutrients;(c) micronutrients;(d) an antioxidant; and(e) nutraceutically acceptable excipients.

2. The composition as claimed in claim 1, wherein the inositols are selected from group consisting of scyllo-inositol, muco-inositol, myo-inositol, neo-inositol, D- chiro-inositol, preferably myo-inositol, neo-inositol, D-chiro-inositol, more preferably myo-inositol and D-chiro-inositol.

3. The composition as claimed in claim 2, wherein the inositols are present in the range of 1 g to 35 g per 100 g, preferably from 1 g to 25 g per 100 g, more preferably from 1 g to 20 g per 100 g of the composition.

4. The composition as claimed in claim 1, wherein the macronutrients are selected from group consisting of carbohydrates, proteins, fats, and fibers.

5. The composition as claimed in claim 4, wherein the carbohydrates are selected from group consisting of cereals like rice, wheat, millet, maize, sorghum, and components like glucose, sucrose, sorbitol, xylitol, maltitol, trehalose, maltodextrin, processed starch, amylose starch, tapioca starch, fructose, lactose, gums or combinations thereof, more preferably skimmed milk powder and gums or combinations thereof.

6. The composition as claimed in claim 4, wherein the carbohydrates are present in the range of 20 g to 70 g per 100 g, preferably 25 g to 65 g per 100 g, more preferably 30 g to 60 g per 100 g of the composition.

7. The composition as claimed in claim 4, wherein proteins are selected from group consisting of concentrates, isolates and hydrolysates of one or more of casein,caseinates (including sodium, calcium, potassium caseinates), whey protein ,milk protein , skimmed milk, soy protein, pea protein, canola protein, wheat and fractionated wheat proteins, corn and its fractions including zein, rice, oat, potato, peanut, green pea powder, green bean powder and the like or combinations thereof more preferably skimmed milk powder, soybean flour, defatted soybean flour, soy proetein isolate, gram flour, ragi flour or combinations8. The composition as claimed in claim 4, wherein the proteins are present in the range of 5 g to 65 g per 100 g preferably 10 g to 55 g per 100 g more preferably 15 g to 45 g per 100 g of the composition.

9. The composition as claimed in claim 4, wherein lipids / fats are selected from group consisting of soy based ingredients, nuts, oilseeds, vegetable oils or combinations thereof, preferably, olive oil, hazelnut oil, palm oil, sunflower oil, high oleic sunflower oil, safflower oil, soybean oil, coconut oil, sesame oil, pumpkin seed oil, peanut oil, mustard oil, linseed oil, corn oil, rice bran oil or and the like or combinations thereof, more preferably, high oleic sunflower oil powder, soya fat powder or combinations thereof.

10. The composition as claimed in claim 4, wherein the fats are present in the range of 1 g to 45 g per 100 g, preferably 3 g to 30 g per 100 g, more preferably 5 g to 20 g per 100 g of the composition.

11. The composition as claimed in claim 4, wherein the fibers are selected from group consisting of soluble fiber, prebiotic fiber, functional fiber, resistant starch, insoluble fiber, preferably soluble fiber, prebiotic fiber, functional fiber, more preferably prebiotic fiber.

12. The composition as claimed in claim 4, wherein the fibers are present in the range of 1g to 30 g per 100g, preferably 1 g to 20 g per 100 g, more preferably 1 g to 15 g per 100 g of the composition.

13. The composition as claimed in claim 1, wherein the micronutrients are selected from group consisting of vitamins, minerals or combinations thereof.

14. The composition as claimed in claim 13, wherein the vitamins are selected from group consisting of vitamin E, vitamin A, vitamin Bl, vitamin B6, vitamin B12, vitamin C, vitamin D2, preferably vitamin E, vitamin A, vitamin B6, vitamin D2, more preferably vitamin E, vitamin B6, vitamin D2.

15. The composition as claimed in claim 14, wherein vitamins are in the range of 2 mg to 25 mg per 100g, preferably 4 mg to 20 mg per 100g, more preferably 6 mg to 15 mg per 100g of the composition.

16. The composition as claimed claim 1, wherein the antioxidant is selected from group consisting of alpha-lipoic acid (ALA), vitamin C, vitamin E, lipoic acid, betacarotene, and carotenoids or combinations thereof.

17. The composition as claimed in claim 16, wherein the antioxidant component is alpha-lipoic acid (ALA).

18. The composition as claimed in claim 17, wherein ALAis in the range of 100 mg to 1200 mg per 100g, preferably 150 mg to 1100 mg per 100g, more preferably 200 mg to 1000 mg per 100g of the composition.

19. The composition as claimed in claim 18, wherein the alpha-lipoic acid (ALA) is encapsulated with encapsulating agent(s) consisting of chitosan, cyclodextrin, alginic acid, soy phosphatidylcholine, egg lecithin, cholesterol, Tween 20, Tween 60, Tween 80, poly ethylene oxide, gelatin, HPMC, calcium caseinate, sodium alginate, silicon dioxide, povidone or combinations thereof.

20. The composition as claimed in claim 19, wherein the encapsulating agent consists of alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin or combinations thereof.

21. The composition as claimed in claim 19, wherein the encapsulating agent is gamma- cyclodextrin.

22. The composition as claimed in claim 17 and 21, wherein the alpha-lipoic acid and gamma-cyclodextrin are present in the ratio of 1 : 1 to 1 :6.

23. The composition as claimed in claim 17, wherein the alpha-lipoic acid (ALA) is encapsulated with cyclodextrin by a process comprising spray drying and wet granulation.

24. The composition as claimed in claim 1, wherein the inositols and macronutrients are present in the ratio of 1 : 10 to 1 :25.

25. The composition as claimed in claim 1, wherein the inositols and micronutrients are present in the ratio 1:0.01 to 1: 0.5.

26. The composition as claimed in claim 1, wherein the inositols and antioxidant are present in the ratio of 1 :0.1 to 1 :5.

27. The composition as claimed in claim 1, wherein the composition can be used as a substitute for at least one meal of a day.

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