HYPOTHYROIDISM

FIELD OF THE INVENTION

The present invention, in general, relates to a nutraceutical composition comprising iodine, selenium, vitamin D3, lycopene and/or other ingredients in a particular amount, which is suitable for the prevention and treatment of hypothyroidism in pregnant women during pregnancy and post pregnancy as well as for the prevention and treatment of hypothyroidism in infertile women.

BACKGROUND OF THE INVENTION

The thyroid gland is a butterfly-shaped endocrine gland that is normally located in the lower front of the neck. The thyroid’s job is to make thyroid hormones, which are secreted into the blood and then carried to every tissue in the body. The Thyroid hormones play a major role in human body’s growth, maturation and metabolic process. The hormones produced by the thyroid gland are triiodothyronine (T3), thyroxine (T4), and calcitonin. T3 and T4 are critical for a normal metabolism and normal brain function, while calcitonin promotes normal bone growth. Every cell in the body depends upon thyroid hormones for regulation of their metabolism. Thyroid hormones regulate many bodily functions, namely the following:

• Metabolism Rate;

• Heart Function;

• Functioning of the Digestive System;

• Muscle Control;

• Brain Development;

• Maintenance of Good Bone Health;

• Maintaining Hormonal Balance; etc. Till date, the most prevalent diseases related to the thyroid gland are the following:

Goiter and Thyroid Nodules - Abnormal enlargement of and/or a Lump in the thyroid gland;

Hyperthyroidism - Excess Level of Thyroid Hormones;

- Hypothyroidism - Low Level of Thyroid Hormones;

Autoimmune Thyroiditis or Hashimoto’s Disease - Antibodies attacking the thyroid cells; and

Cancer of the thyroid

Hypothyroidism is a disease condition in which the thyroid gland does not produce enough thyroid hormone. Deficiency of thyroid hormones can adversely affect normal body functions such as Heart rate, body temperature and all aspects of metabolism. Common causes are Iodine deficiency, auto-immune disease such as Hashimoto’s thyroiditis, surgical removal of the thyroid and pregnancy.

Thyroid hormones are crucial for normal development of a baby’s brain and nervous system. Maternal thyroid hormones or the hormones of the mother have a great impact on maternal outcome as well as on the foetal growth and development of the baby. The thyroid hormones circulating in the plasma exist in bound form [bound to thyroglobulin- TBG] and free form [Free T3 and Free T4] Pregnancy is a goitrogenic condition, that is, increased circulating estrogen increases serum levels of thyroglobulin thereby increasing the bound form and decreasing the free thyroid hormone levels in turn stimulating increase in serum Thyroid Stimulating Hormones [TSH] levels. On the other hand, human chorionic gonadotropin [HCG] mimics TSH and causes a transient decrease in serum TSH levels at around 8 to 14 weeks of gestation.

The foetus starts to produce thyroid hormones from 8-10 weeks gestation but provides significant amount after mid-gestation. The maternal thyroid hormones transferred via placenta are the main source for foetal growth and development. Thyroid hormones are critical for the normal foetal brain development, neuronal multiplication, migration and organization. Pregnancy is a period that places great physiological stress on both the mother and the foetus in the best of times. However, if pregnancy is compounded by endocrine disorders such as hypothyroidism, the potential for maternal and foetal adverse outcomes can be immense. Hypothyroidism is widely prevalent in pregnant women and the rate of detection, especially in a developing country like India, has not kept pace with the magnitude of the problem. Since hypothyroidism is easily treated, timely detection and treatment of the disorder could reduce the burden of adverse foetal and maternal outcomes, which are very commonly encountered.

Thyroid physiology is perceptibly modified during normal pregnancy. These alterations take place throughout gestation, help to prepare the maternal thyroid gland to cope with the metabolic demands of pregnancy, are reversible post-partum and the interpretation of these changes can pose a challenge to the treating physician.

The most notable change is the increase in thyroxine-binding globulin (TBG). This begins early in the first trimester, plateaus during midgestation, and persists until shortly after delivery. This is due to stimulation of TBG synthesis by elevated maternal estrogen levels, and more importantly, due to a reduced hepatic clearance of TBG because of estrogen-induced sialylation.[l] This increased TBG concentration leads to an expansion of the extra-thyroidal pool and results in elevated total T3 and T4 levels due to an increase in maternal thyroid hormone synthesis. Maternal thyroid hormone synthesis is also increased due to an accelerated renal clearance of iodide resulting from the increased maternal glomerular filtration rate.

Enhanced metabolism of T4 in the second and third trimesters, due to a rise in placental type II and type III deiodinases, which convert T4 to T3 and T4 to reverse T3 and T2 respectively, act as further impetus to T4 synthesis. Plasma iodide levels decrease due to both increased thyroxine metabolism and increased renal iodide clearance. All these changes lead to an increase in the size of the thyroid gland in 15% of pregnant women, which returns to normal in the post-partum period.

Serum hcG has intrinsic thyrotropic activity, which increases after fertilization and peaks at 10 to 12 weeks. Hence, in the first trimester, free T3 and T4 levels increase slightly and TSH levels decrease in the first trimester with a readjustment in the second and third trimesters, when hCG levels decrease. As a consequence, cut-offs to determine hypothyroidism in pregnancy are different in the first trimester and the rest of the pregnancy.

Pregnancy induced hypothyroidism has become one of the inevitable complications in pregnancy. Thyroid problems can be hard to diagnose in pregnancy due to higher levels of thyroid hormones and other symptoms that occur in pregnancy and thyroid disorders. During pregnancy, the size of thyroid gland is increased by 10% - 20 %, with hcG (a pregnancy hormone) stimulating thyroid hormone production. Further, increased estrogen produces higher level of thyroxine-binding globulin, a protein that transports thyroid hormone in the blood.

The main changes in thyroid function associated with pregnancy are due to an increase in hormone requirements in first trimester. And thyroid hormones regulate secretion and function of other hormones. If it is not treated timely, it may lead to miscarriage, preeclampsia, fetal brain damage and congenital hypothyroidism. In the case of a baby resulting out of pregnancy of a mother suffering from hypothyroidism, there is an increased risk of the baby’s well-being and such a baby could be associated with any one or all the following:

Placental Abnormalities

Preeclampsia

Miscarriage

Stillbirth

Preterm Birth

Low-birth Weight

Mental Retardation

Neurocognitive Deficits

Congenital Hypothyroidism

There is also a link between hypothyroidism and infertility in women. Low levels of the thyroid hormone can interfere with the release of egg from the ovary (ovulation), which impairs fertility. About 30% of infertility cases are reported due to thyroid dysfunction, which seeks the immediate attention to focus on thyroid health to enhance fertility.

It has been estimated that about 42 million people in India suffer from thyroid dysfunction, with higher prevalence during pregnancy. There are several treatments of hypothyroidism such as use of the synthetic thyroid hormone, levothyroxine. This oral medication restores adequate hormone levels, reversing the signs and symptoms of hypothyroidism.

Treatment of hypothyroidism in Ayurveda is also available, which involves clearing these channels in order to balance the body’s energies and restore the circulation of thyroxin, Herbal preparations are administered to increase the digestive fire at a cellular level, restoring proper metabolism. Diet and lifestyle advices are also given.

Besides several available treatments, none of them has proven to be acting on the root cause of thyroid dysfunction and towards its prevention.

Levothyroxine is a synthetic T4 hormone which overcomes the deficiency of thyroid hormones in patients with the symptoms of thyroid dysfunction.

Thus, it is challenging to work in a segment where preventing a complication is at prominence rather than its treatment.

Against this backdrop, the present inventors have arrived at a nutraceutical composition comprising iodine, selenium, vitamin D3, lycopene and/or other ingredients in a particular amount, which is a root cause treatment of thyroid dysfunction and suitable for the prevention and treatment of hypothyroidism in pregnant women during pregnancy and post pregnancy as well as for the prevention and treatment of hypothyroidism in infertile women, which forms the basis of the present invention.

EP 2929879A1 discloses a combination preparation comprising at least the active ingredients C-vitamin, E-vitamins, B1 -vitamin, B2-vitamin, B5-vitamin, B6-vitamins, B7-vitamin, B9-vitamin, B12 Vitamins, niacin, zinc, iron, selenium, iodine, copper, N- acetylcysteine, lycopene, omega-3 fatty acids, ubiquinone- 10, and optionally D-vitamins, characterized in that lycopene in an amount with a lower limit of 8 mg is contained in the combination preparation. However, this combination preparation is reported to be useful in the treatment of endometriosis-associated female subjects and for improvement of female infertility but fails to disclose use of given combination preparation for treatment of thyroid dysfunction during pregnancy.

WO 2012076680A1 also disclose a combination preparation for improving oocyte quality and egg maturity comprising at least the active ingredients C vitamins, E vitamins, B1 vitamins, B2 vitamins, B5 vitamins, B6 vitamins, B9 vitamins, B12 vitamins, D vitamins and at least a ubiquinone- 10 component, characterized in that B7 vitamins are included. However, this combination preparation, which is primarily a combination of all sorts of vitamins and a ubiquinone component as active ingredients is reported to be useful, for improving oocyte quality and egg maturity, but fails to disclose use of given combination preparation for treatment of thyroid dysfunction during pregnancy.

US 6299896B1 discloses a multivitamin and mineral supplement comprising from about 5000 I.U to about 10,000 I.U. of vitamin A; from about 1000 mg to about 2000 mg of vitamin C; about 400 I.U. of vitamin D; from about 800 I.U. to about 1200 I.U. of vitamin E; about 25 meg of vitamin K; about 3 mg of vitamin Bl; about 10 mg of vitamin B2; about 20 mg of vitamin B3; about 25 mg of vitamin B6; about 800 meg of folic acid; about 400 meg of vitamin B12; about 300 meg of biotin; about 10 mg of pantothenic acid; up to about 18 mg of iron dosed in the form of a pharmaceutically acceptable iron compound; about 150 meg of iodine dosed in the form of a pharmaceutically acceptable iodine compound; about 400 mg of magnesium dosed in the form of a pharmaceutically acceptable magnesium compound; about 15 mg of zinc dosed in the form of a pharmaceutically acceptable zinc compound; from about 100 meg to 200 meg of selenium; about 2 mg of copper dosed in the form of a pharmaceutically acceptable copper compound; about 100 meg of chromium dosed in the form of a pharmaceutically acceptable chromium compound; about 400 mg of potassium dosed in the form of a pharmaceutically acceptable potassium compound; about 500 mg of choline dosed in the form of a pharmaceutically acceptable choline compound; about 10 mg of lycopene; and about 50 mg co-enzyme Q-10 dosed in the form of a pharmaceutically acceptable co enzyme Q-10 compound.

However, this combination preparation is reported to be useful as a multi-vitamins and mineral supplement tailored menopausal, post-menopausal women, pre-menopausal women and athletes, which supplies the right amount of the right micronutrients at the right time to assure adequate intake of micronutrients needed for disease prevention and protection against nutritional losses and deficiencies due to lifestyle factors and common inadequate dietary factors. This report, however, does not specifically disclose the use of claimed multivitamin and mineral supplements in suitable concentration range to treat hypothyroidism in pregnant and infertile women.

US 2004213857A1 discloses a dosage form, consisting of, one or more vitamins, one or more minerals selected from the group consisting of Iron, Zinc, and Magnesium, one or more trace elements selected from the group consisting of Chromium, Copper, Iodine, Molybdenum and Selenium, DHA for consumption of pregnant women, lactating women or women of childbearing potential that are attempting to become pregnant, to overcome Multi-vitamin and mineral deficiencies. However, the pharmaceutical or dietary composition disclosed in US 2004213857A1 does not claim the usage of the dosage form for treating thyroid dysfunction during pregnancy.

US 8183227B1 discloses a composition consisting of vitamin D in an amount of 1000 I.U. and iodine in an amount of about 150 pg along with other component which is used for female before pregnancy, during pregnancy, after pregnancy, while breast-feeding, or a combination thereof as nutrition supplementation.

But the composition disclosed in US 8183227B1 is without selenium, which is an essential component in the present invention composition. Selenium plays important role in recycling of iodine in body, therefore, suitable amount of selenium given along with iodine helps to minimize the dosage of Iodine as found by the present inventors.

US 2019021385A1 discloses an orally dissolvable composition for administration to a pre natal, pregnant, post-natal or breastfeeding subject comprising a first water-soluble film comprising one or more vitamins and minerals selected from the group consisting of vitamin A, vitamin C, vitamin D3, vitamin E, vitamin B2, niacin, vitamin B6, folic acid, vitamin B12, iron, iodine, magnesium, zinc. But, the composition does not contain selenium.

US 20150289553A1 discloses a method of formulating a dietary supplement comprising a series of well-defined steps, which results in having the said ingredients present in a safe and effective proportion. However, the disclosure in US 20150289553A1 does not claim the usage of the dosage form for treating thyroid dysfunction during pregnancy.

US 10092545B2 disclose a single-unit nutritional supplement composition for improving female fertility comprising an effective amount of a combination of myo-inositol, d-chiro- inositol, melatonin, n-acetyl 1 -cysteine, Resveratrol, Choline, Benfotiamine, and coenzyme Q10. The nutritional supplement in the composition is reported to further comprise an antioxidant, vitamins, minerals or a combination thereof.

However, the single-unit nutritional supplement composition disclosed in US 10092545B2 relates to a method for improving egg quality, ovarian function, overall female fertility, but does not specifically relate to the usage of the composition for treating thyroid dysfunction during pregnancy. US 8703716B2 disclose method for providing sialic acid to a female, wherein the sialic acid is in the form of n-acetylneuraminic acid, comprising administering sialic acid to the female during at least one of the stages of preconception, pregnancy and lactation, wherein the sialic acid provides a developmental benefit to a foetus or child of the female.

However, the nutraceutical composition of the present invention does not comprise any sialic acid component and the composition disclosed in US 8703716B2 relates to a utility during preconception, pregnancy and lactation but does not specifically relate to the usage of the composition for treating thyroid dysfunction during pregnancy.

US 20070059378A1 disclose a method of treating a female mammal experiencing hot flushes comprising administering to said mammal a composition comprising a mixture of an isoflavone, an isoflavone synergist, and a methylation support compound.

It would thus be seen that any of the prior art document cited above fail to disclose the composition comprising combination of iodine, selenium, lycopene, vitamin D3 and other ingredients in appropriate proportions, used particularly for treatment of hypothyroidism during pregnancy and in infertile women as in the present invention.

The nutraceutical composition developed by the present inventors fills the void existing in the current therapy regimen and plays a vital role to prevent and cure inevitable complications of pregnancy due to thyroid dysfunction which may lead to serious health issues to the mother as well as the infant.

OBJECTS OF THE INVENTION

Accordingly, an object of the present invention is to provide a nutraceutical composition comprising iodine, selenium, vitamin D3, lycopene, and/or other ingredients in appropriate and specific proportion, which is suitable for the prevention and treatment of hypothyroidism.

An another object of the present invention to provide a nutraceutical composition comprising iodine, selenium, vitamin D3, lycopene, and/or other ingredients in appropriate and specific proportion, which is suitable for the prevention and treatment of hypothyroidism during pregnancy, post pregnancy and infertile women.

Yet further object of the present invention is to provide a nutraceutical composition comprising iodine, selenium, vitamin D3, lycopene, and/or other ingredients in appropriate and specific proportion, which is suitable for the treatment of thyroid dysfunction.

Still further object of the present invention is to provide a nutraceutical composition comprising iodine, selenium, vitamin D3, lycopene, and/or other ingredients in appropriate and specific proportion, which is suitable for the treatment of thyroid dysfunction during pregnancy, post pregnancy and in infertile women.

Further object of the present invention is to provide a nutraceutical composition comprising iodine, selenium, vitamin D3, lycopene, and/or other ingredients in an appropriate and specific proportion, presented in the form of tablets, capsules, or syrup. yet further object of the present invention is to provide a nutraceutical composition comprising iodine, selenium, vitamin D3, lycopene, and/or other ingredients in appropriate and specific proportion, presented in the form of capsules for oral administration, to be taken as one capsule once daily, ideally one-hour after a meal for supplementing the dietary needs of pregnant women during pregnancy and post pregnancy and in infertile women for the prevention and treatment of hypothyroidism.

SUMMARY OF THE INVENTION The present invention provides a nutraceutical composition comprising a combination of Iodine, selenium, lycopene, vitamin D3 and other ingredients in specific proportions, used particularly for treatment of hypothyroidism during pregnancy, post pregnancy and in infertile women.

In an embodiment of the present invention, the nutraceutical composition comprising iodine, selenium, vitamin D3 and lycopene as active ingredients and other ingredients in specific proportion for the prevention and treatment of hypothyroidism.

In another embodiment of the present invention, the nutraceutical composition comprising iodine, selenium, vitamin D3 and lycopene as active ingredients in the ratio of 1-2 : 2- 4 : 4.1- 5: 80 - 95 - and other ingredients for the prevention and treatment of hypothyroidism

More particularly the nutraceutical composition comprising iodine, selenium, vitamin D3 and lycopene as active ingredients in the ratio of 1.8 : 3.6 : 4.5 : 90 and other ingredients (please specify proportion) for the prevention and treatment of hypothyroidism. In another embodiment of the present invention, the nutraceutical composition comprising 50-100 meg iodine, 100-250mcg selenium, 500-2000 IU vitamin D3 (1 IU = 0.25 meg) and 4000-6000 meg lycopene as active ingredients and other ingredients in specific proportion for the prevention and treatment of hypothyroidism. In yet another embodiment of the present invention, the nutraceutical composition comprising 100 meg iodine, 200 meg selenium, 1000 IU vitamin D3 and 5000 meg lycopene as active ingredients and other ingredients in specific proportion per unit dosage for the prevention and treatment of hypothyroidism.

In still another embodiment of the present invention, the nutraceutical composition further comprising wherein the other ingredient is Vitamin C.

In a further embodiment of the present invention, the nutraceutical composition is in the form of tablets, capsules or syrup.

In yet another embodiment of the present invention, the nutraceutical composition is in the form of tablets.

In yet another embodiment of the present invention, said tablets to be taken once daily one-hour after a meal, or as a fixed measurement of the syrup to be taken once daily, ideally one-hour after a meal.

In still another embodiment of the present invention, the nutraceutical

composition is in the form of capsules.

In another embodiment of the present invention, the tablets to be taken once daily one hour after a meal, or as a fixed measurement of the syrup to be taken once daily, ideally one-hour after a meal.

In yet another embodiment of the present invention, the nutraceutical composition is in the form of syrup.

In an embodiment of the present invention, the said syrup to be taken as a fixed measurement once daily one-hour after a meal.

In another embodiment there is provided a process of producing the composition comprising mixing iodine, selenium, vitamin D3 and lycopene as active ingredients so as to form the nutraceutical composition having iodine, selenium, vitamin D3 and lycopene, in the ratio of 1-2 : 2- 4 : 4.1- 5: 80 - 95 , preferably in the ratio of 1.8 : 3.6 : 4.5 : 90 per unit dosage. The nutraceutical composition of the present invention, at the dose specified hereinbefore is found to be highly effective and useful for prevention and treatment of the following indications:

- Pregnancy induced hypothyroidism and sub-clinical hypothyroidism;

- Hypothyroidism;

Infertility;

- Fetal Neurocognitive Development; and

- Hormonal dysfunction and Menstrual Irregularity.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: Column chart showing mean levels of each parameters in Placebo and Treatment group.

Figure 2: Horizontal bar chart showing number of women with different complications.

Figure 3: Pie chart showing distribution of women according to diagnosis.

Figure 4: Pie chart showing distribution of women according to month of diagnosis. Figure 5: Column chart with error bars showing mean TSH levels in two study groups at pre and post times.

Figure 6: Column chart showing mean TSH levels in two study groups at pre and post times according to diagnosis.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a nutraceutical composition comprising iodine, selenium, vitamin D3, lycopene and/or other ingredients in a particular amount, which is suitable for the prevention and treatment of hypothyroidism in pregnant women during pregnancy and post pregnancy as well as for the prevention and treatment of hypothyroidism in infertile women.

The nutraceutical composition comprises 100 meg iodine, 200 meg selenium, 1000 IU vitamin D3, 5000 meg lycopene, and/or other ingredients, which is suitable for the treatment of thyroid dysfunction during pregnancy, post pregnancy and also in infertile women.

The nutraceutical composition comprising iodine, selenium, vitamin D3, lycopene, and/or other ingredients in appropriate and specific proportion, presented in the form of tablets, capsules, or syrup, preferably capsules for oral administration, to be taken as one capsule or tablet once daily, ideally one-hour after a meal, or as a fixed measurement of the syrup to be taken once daily, ideally one-hour after a meal.

The nutraceutical composition comprising 100 meg iodine, 200 meg selenium, 1000 IU vitamin D3, 5000 meg lycopene, and/or other ingredients, presented in the form of tablets, capsules, or syrup, preferably capsules for oral administration, to be taken as one capsule or tablet once daily, ideally one-hour after a meal, or as a fixed measurement of the syrup to be taken once daily, ideally one-hour after a meal.

The nutraceutical composition comprising 100 meg iodine, 200 meg selenium, 1000 IU vitamin D3, 5000 meg lycopene, and/or other ingredients, presented in the form of tablets, capsules, or syrup, preferably capsules for oral administration, to be taken as one capsule or tablet once daily, ideally one-hour after a meal, or as a fixed measurement of the syrup to be taken once daily, ideally one-hour after a meal, for supplementing the dietary needs of pregnant women during pregnancy and post pregnancy and in infertile women for the prevention and treatment of hypothyroidism.

The significance and/or usefulness of each one of the ingredients of the nutraceutical composition of the present invention and the significance of the quantities of each one of the ingredients of the nutraceutical composition the present invention is detailed as under:

IODINE:

Iodine is an essential component of thyroid gland for production of T3 and T4 and to ensure normal thyroid function. To meet the demand, thyroid gland traps iodine from blood and in combination with Tyrosine (a non-essential amino acid present in thyroid gland) synthesizes T3 and T4. Iodine is the natural root cause treatment for thyroid dysfunction rather than getting L- Thyroxin which is synthetic replacement for T4.

The thyroid economy undergoes a series of metabolic changes during pregnancy and lactation. One of the factors involved in these changes is the increased requirement of iodine in the mother due to the transfer of thyroxine (T4) and of iodide from mother to foetus during pregnancy and to the loss of iodide in breast milk during lactation. These two processes are required in order to ensure normal brain development and prevention of mental retardation in the offspring.

Iodine has more profound effect in thyroid dysfunction than other conventional treatment available in market i.e. L-thyroxin. L-thyroxin is a synthetic replacement for T4 and needs a long-term treatment, also the chances of recurrence is higher with L- thyroxine treatment.

- Iodine is a root cause treatment for thyroid gland dysfunction.

- Iodine regularizes thyroid hormones (T3 and T4) synthesis, treats and prevents hypothyroidism. Also, the chances of recurrence are minimal.

- Iodine helps in regulating secretion and function of hormones thus ensure healthy pregnancy and enhances fertility.

- Iodine plays a vital role in foetal brain development.

Consequences of Iodine deficiency in Pregnancy

- Hypothyroidism in pregnancy is associated with increased risk of preeclampsia, placental abnormalities, miscarriage, stillbirth, preterm birth, low-birth weight, neurocognitive deficits and congenital hypothyroidism.

Iodine participates in the development of baby’s brain and central nervous system therefore even a slight iodine deficiency during pregnancy can cause irreversible foetal brain damage. Maternal hypothyroidism increases foetal risk of mental retardation, dyslexia, ADHD

Alzheimer’s disease decreased child survival and apathetic children with lowered capacity for movement and speech. The thyroid and infertility

Thyroid hormones have profound effects on reproduction and pregnancy. WHO says, “iodine deficiency decreases fertility and increases foetal mortality”.

Thyroid-related fertility problems in women

Thyroid disease is a common endocrine disorder in women of childbearing age.

Thyroid hormones are closely interacting with the female reproductive hormones to preserve normal function of the ovaries and maturation of the egg (oocyte).

- Dysfunctions of the thyroid gland can alter the balance of reproductive hormones.

Iodine in female Infertility

o Ensure ovulation

o Helps in oocyte maturation.

o Regulate secretion and function of Luteinizing Hormone

o Remove ovarian cyst and cure PCOS.

o Regulates secretion and function of ovarian hormones.

Thyroid-related fertility problems in men

Disturbances in the thyroid function could affect men fertility. Thyroid hormones, previously thought not to affect male fertility, are now being recognized as having an important role in sperm production.

Proper diagnosis and treatment to return a man to“normal” thyroid function was found to reverse most infertility symptoms in men.

WHO/UNICEF/ICCIDD recommend an iodine intake of 200 - 250 mcg/day for pregnant women, 150 mcg/day for non-pregnant women and 290 meg / day for lactating women.

Etiology of Iodine Deficiency in India

^■ Iodized salt contains 74 meg of iodine / gram of salt, which does not meet the recommended daily allowance of 150 meg in normal adult and 250 meg in pregnant women.

^■ Food fortification with bromine, a substance that opposes iodine, especially Bakery products. ^■ The Indian soil is more iodine-deficient because of high rainfall and flooding, leading to mineral depletion. (National Iodine Deficiency Disorders Control Program).

^■ Increased usage of cell phones and smart meters reduces iodine level (according to International Journal of Radiation Biology).

The present inventors have now found that the composition of the present invention having less amount of iodine to provide the desired effect

SELENIUM:

The thyroid system regulates and maintains many vital functions in the body. To ensure its optimal functioning, the thyroid gland requires adequate levels of iodine and selenium. Iodine and Selenium are important to ensure a proper balance between levels of thyroid hormones.

Iodine atoms attach to a tyrosine“backbone” to produce T3 and T4 hormones. T3 (triiodothyronine) contains 3 iodine atoms per molecule. T4 (thyroxine) contains 4 iodine atoms per molecule. T3 is considered the active form of this hormone, used by the body to regulate metabolism. Most of this hormone is stored in the form of T4 until it is required to be active. T4 becomes T3 via a process called deiodination. Selenium-based deiodinase enzymes are needed to facilitate deiodination.

Selenium deficiency can cause inadequate T4-to-T3 conversion; possibly leading to low thyroid activity (hypothyroidism). This is because seleno-proteins play a vital role in T3 conversion. This is a condition which can have several negative effects on the human body, including chronic low energy levels, poor skin health, impaired cognitive function and impaired detoxification function.

Selenium is an essential micronutrient and plays an active role in enhancing the immunity and metabolism. It also improves fertility and reduces the risk of autoimmune disease and cancer, in addition to thyroid disease. Selenium is a component of the amino acid selenocysteine. We need selenocysteine for synthesis of 25 identified seleno proteins that have a variety of biological functions. Selenium plays an important role in the health and function of the thyroid gland. Along with iodine, selenium is used to support the production of T3 and T4 thyroid hormones. T3 and T4 are used by all cells in the body to facilitate energy metabolism; they play an indirect role in several important biological and neurological functions.

Low levels of selenium make it harder for the thyroid to make its hormones and for the body to convert thyroid hormones into the form that’s needed by human cells. That is because selenium is a fundamental component of various seleno-proteins, which are needed by the body to form thyroid hormones and to use them. The various ways in which the nutrient affects thyroid function include:

The regulation of thyroid hormone production.

Supporting the conversion of thyroxine (T4, the hormone produced in greatest quantities by the thyroid) to triiodothyronine (T3, the bioactive thyroid hormone that increases human cells’ basal metabolic rate).

Protecting the thyroid’s tissues whenever the thyroid is affected by oxidative stress.

Regulates levels of thyroid hormone in the body.

In addition to its roles in maintaining proper thyroid function, selenium is also important for health in several other ways. Selenium is the base of more than two dozen seleno-proteins which are involved in DNA synthesis and repair, resisting damage from oxidative stress, promoting immune function and in reproduction.

The enzymes seleno-de-iodinase formed with selenium helps control the level of T3 in organs including brain, kidney, and liver. Glutathione peroxidase is another selenium enzyme that helps balance the level of T4 and prevents it from increasing above its normal limit.

The role of selenium in normal and abnormal thyroid function

Selenium is more densely concentrated in the thyroid gland than in any other tissue in the body. Selenium is so important to thyroid function that the body preferentially distributes selenium to the thyroid and preferentially expresses the thyroid seleno-proteins.

Eleven seleno-proteins are expressed that protect the thyroid gland against damage by harmful radicals that are produced during the biosynthesis of thyroid hormone.

- Low selenium status is associated with increased risk of goitres (enlargements of the thyroid gland) and thyroid nodules (lumps in the thyroid gland, some of which are malignant).

Evidence from some clinical studies indicates that individuals with low baseline selenium status diagnosed with autoimmune thyroid disease may benefit from selenium supplementation.

Selenium supplementation may reduce the extent of the damage to cells caused by the binding of lymphocytes and/or thyroid autoantigens to thyroid cell membranes.

Selenium supplementation and autoimmune thyroid diseases or Hashimoto’s disease

A study published in Jhumannal of Clinical Endocrinology and Metabolism in 2002 indicates that even mild deficiency of selenium can lead to autoimmune disease in the thyroid or Hashimoto’s disease.

Hashimoto’s disease is an autoimmune disease in which the immune system’s T- cells mistakenly attack the thyroid gland, especially the thyroid peroxidase enzymes. Hashimoto’s disease causes the following symptoms in the thyroid gland: · Chronic inflammation.

• Damage to the thyroid tissue.

• Reduced thyroid activity (hypothyroidism).

A 2014 Cochrane review of clinical studies involving selenium supplementation in addition to iodine therapy showed that the selenium supplementation is associated with a reduction in the concentrations of circulating autoantibodies. Selenium supplementation of patients with autoimmune thyroid diseases is associated with the following beneficial health effects:

- Reductions in anti-thyroperoxidase antibody concentrations.

Improved thyroid ultrasound images. Improved quality of life.

The thyroid peroxidase enzymes play an important role in the production of thyroid hormones. In autoimmune diseases, the body mistakenly produces antibodies that attack these important enzymes. Adequate selenium status seems to reduce the risk of these mistaken autoimmune attacks.

- Low dietary selenium intake is associated with increased prevalence of autoimmune thyroid diseases in patients.

Selenium supplementation decreases circulating thyroid autoantibodies in patients with autoimmune thyroiditis.

Selenium’s modulation of immune system response may involve reduced release of inflammatory cytokines.

- More research is needed into the effects of selenium supplementation on the restoration of normal thyroid function and on patients’ quality of life.

Iodine and selenium:

Selenium also plays a significant role in iodine levels by its involvement in recycling of iodine in body, therefore, suitable amount of selenium along with iodine will help to optimize the iodine amount (which may help avoid the excess amount of iodine) in composition. When a person has low levels of both the nutrients, there is a high possibility of imbalance in thyroid function to occur. In such cases, it is recommended to treat the deficiency of both nutrients to get the thyroid back to the normal condition.

Selenium and Thyroid Nodules:

Thyroid nodules are abnormal growth in thyroid cells that cause lumps in the thyroid gland. Hashimoto’s disease is an autoimmune disorder where the immune system attacks cells in the thyroid gland. Hashimoto’s is linked to increased risk of developing thyroid nodules. These nodules are also caused by iodine deficiency.

Selenium is a component of Selenoproteins including the Glutathione peroxidase (GPx), thioredoxin reductases (TRxs) and the iodothyronine deiodinases (DIs).

GPx prevents the accumulation of damaging peroxides in the thyroid (Peroxides impairs the peripheral deiodination process required to generate the active thyroid hormone, T ₃ , from T _4. ) and indirectly helps to limit T4 when its levels get too high.

DIs are a subfamily of deiodinase enzymes important in the activation and deactivation of thyroid hormones. Thyroxine (T4), the precursor of 3,5,3'-triiodothyronine (T3) is transformed into T3 by deiodinase activity and maintain appropriate T3 levels in the thyroid, liver, kidney and brain cells

There have been numerous studies conducted which involves selenium supplementation during pregnancy._Many clinical trials have been conducted in pregnant women with AIT (Autoimmune Thyroiditis). AIT in pregnant women not only puts them at increased risk for miscarriage, preterm delivery, and postpartum thyroiditis (PPT), but also results in 50% of cases in overt thyroid disease during the first postpartum year. Their risk is also higher for progressive development of hypothyroidism during gestation. Moreover, women who had an abortion had significantly lower selenium content than controls. Selenium concentration varies during pregnancy but tends to be lower in the third trimester, indicating that women with low selenium intake may be exposed to high risk during pregnancy. It can be inferred that determination of selenium status and selenium supplementation could be of importance in the management of thyroid disease in pregnancy [Selenium and the Thyroid: A Close-Knit Connection; Leonidas H Duntas; The Journal of Clinical Endocrinology and Metabolism, Volume 95, Issue 12, 1 December 2010, Pages 5180-5188]

In this respect the present invention providing defined amount of selenium, particularly 200mcg along with iodine (lOOmcg) and components like Vitamin D3 and Lycopene in the formulation has found to provide better activity particularly for treatment of hypothyroidism during pregnancy and in infertile women as in the present invention. VITAMIN D3 [1000 IU or other suitable quantities]:

Thyroid treatment requires additional Vitamin D because Optimum Level of vitamin D is required for cell to take up maximum thyroid hormone. Hypothyroidism reduces absorption of vitamin D and other nutrients, which make cells less able to take thyroid hormone and increases further risk of hypothyroidism. Thus, additional Vit D is required for thyroid treatment.

• 94% of Overt Hypothyroid Hashimoto’s patients had Vitamin D deficiency.

• 98% of Subclinical Hypothyroid Hashimoto’s patients had Vitamin D deficiency.

• 86% of Euthyroid Hashimoto’s patients had Vitamin D deficiency.

However providing vitamin D3, in amount of 1000IU in a composition having lOOmcg of iodine, 200mcg of selenium as well as Lycopene in defined amount has been found by the present inventors to act on pregnant woman to achieve the end result, particularly for treatment of hypothyroidism during pregnancy and in infertile women, which has been hitherto unknown.

LYCOPENE [J:

Human body undergoes in many physiological activities and environmental stress causing free radicals as by products. Free radicals cause damage to certain macromolecules including lipids, proteins and most importantly DNA. This damage is called oxidative damage.

Free radicals damage has been linked to a range of disorders including pre- eclempsia, severe complications in pregnancy, cancer, arthritis, Renal diseases, Alzheimer’s disease and diabetes.

Lycopene is most potent and safe antioxidant. Antioxidants neutralize free radicals, helping to prevent cell and tissue damage that could lead to cellular damage and disease. Lycopene reduces risk of preeclampsia. A severe pregnancy complication due to excessive free radicals, characterized by high blood pressure and high protein in urine, causes insufficient transport of oxygen and nutrients through placenta which leads to restricted growth or preterm birth. It may also lead to serious complications including miscarriage or still birth. Incorporating lycopene and that too in amount of 5000 MCG or other suitable quantities in a composition having Iodine, selenium and vitamin D3 in defined amount as mentioned above have been found by the present inventors to achieve end result in pregnant women to combat thyroid deficiency and other related effect on both the woman and child/foetus. More particularly, for treatment of hypothyroidism during pregnancy and in infertile women as in the present invention

OTHER INGREDIENTS

The composition may further optionally contain Vitamin C.

SIGNIFICANCE OF CONCENTRATION OF VARIOUS INGREDIENTS TN THE NEUTRACEUTICAL COMPOSITION OF THE PRESENT INVENTION

Iodine 100 meg:

• WHO/UNICEF/ICCIDD recommend an iodine intake of 200 - 250 meg/day for pregnant women, 150 meg/day for non-pregnant women and 290 meg / day for lactating women i.e. percentage during pregnancy increases by 33% over non-pregnant women.

• The daily requirement of T4 in order to maintain euthyroidism in hypothyroid women increases by 40-60 % during pregnancy. This represents an additional dose of 75 to 150 meg T4/day, i.e. 50 to 100 meg iodine.

• Dietary sources of Iodine are fish, dairy, egg and salt, which provide around 100 - 150 meg per day.

The present inventors have found that less amount of iodine i.e. 100 meg supplementation by way of the composition of the present invention, per unit dosage per day is enough to ensure normal thyroid function, more particularly for treatment of hypothyroidism during pregnancy and in infertile women.

Selenium 200 meg:

The recommended daily intake of selenium is 55 micrograms per day for adults. For pregnant or breastfeeding women, 60 to 70 meg are recommended. The safe upper limit for selenium is 400 meg a day in adults. In studies supporting the use of selenium for prostate cancer prevention, men took 200 meg daily.

However the present inventors have found that providing a composition comprising Selenium supplementation in amount of 200 meg along with iodine, vitamin D3 and lycopene in unit dosage protects the thyroid in TPO-positive women during and after pregnancy, which is unexpected.

Vitamin D3 1000 IU:

Vitamin D31000 IU is standard recommended dose in thyroid dysfunction and foetal development during pregnancy.

The role of vitamin D3 in AITD is known but that vitamin D3 when incorporated into a composition comprising iodine of lOOmcg, selenium of 200mcg and lycopene per unit dosage, would take care of the same along with treatment of hypothyroidism during pregnancy and in infertile women as in the present invention, as found by the present inventors was hitherto unknown.

Lycopene 5000 meg:

Recommended dose is 5000 meg to prevent pre-eclampsia and cellular damage by various societies. In case of normal or fertile women, child is the target of the object therapy. In case of infertile women, mother is the target of the object therapy. The cycle in infertile women is made fertile by the therapy; then goes into pregnancy; then to delivery of baby; after delivery therapy continues.

However, providing the same in the form of a composition having iodine in amount of lOOmcg, Selenium in amount of 200mcg, vitamin D3 in amount of 1000IU and lycopene in amount of 5000mcg in unit dose, particularly for the treatment of hypothyroidism during pregnancy and in infertile women as in the present invention, has been hitherto unknown.

The nutraceutical Composition of the present invention is for oral use and can be in the form of tablet, capsule or syrup. The dose is one tablet/capsule a day so as to provide iodine in amount of lOOmcg, Selenium in amount of 200mcg, vitamin D3 in amount of 1000IU and lycopene in amount of 5000mcg in unit dose.

The nutraceutical composition is provided by mixing the components so that iodine in amount of lOOmcg, Selenium in amount of 200mcg, vitamin D3 in amount of 1000IU and lycopene in amount of 5000mcg are present in unit dose.

The present invention nutraceutical composition disclosed herein can be formulated in various dosage forms such that it is suitable for oral administration.

The embodiments are further described herein by reference to the following examples which are included merely to illustrate and demonstrate the invention. These specific examples should not be construed to limit the scope of the invention in any way.

EXAMPLES

EXAMPLE 1: A Randomized Double Blinded placebo controlled comparative study to evaluate the efficacy and safety of present invention drug on pregnancy induced

Hypothyroidism and Sub-clinical Hypothyroidism patients.

Example 1 A : Preparation of the composition in the form of unit dosage capsules

All the raw materials are tested by QC/QA department and only after the raw materials complies with the standards mentioned they are used.

Manufacturing process involves weighing of all the ingredients and then further taken into processing.

The unit dosage composition is prepared in the form of capsules. The contents of the capsule has three pellets, the first pellets contained Iodine and Vitamin D3, second pellets contained Lycopene co-processed with Linolenic acid and the third pellet contained Selenium. Present invention controlled release capsules avoided Lycopene destroyed in gastric acid, and positioned in the intestinal tract, in order to achieve rapid onset, the purpose of improving bioavailability and enhanced the absorption of Iodine in stomach due to immediate release and lastly targeted release of Selenium in colon.

Preparation of the capsule comprising the steps of preparing:

(i) Preparing a first pellets:

a, by taking the ratio of each raw materials viz., Iodine & Vitmain D3 b, the components of the active-containing layer is configured to mix the active containing layer coating solution, the active containing layer coating solution with the active, then granulated and dried;

c, the isolation layer packet, mixing the components of the separation layer is configured to release layer coating liquid, the coating liquid for release layer on the pellet cores obtained in step b, and dried;

d, enteric coated layer, the configuration of the components into the enteric coating layer of enteric coating solution, a coating solution for enteric coating on the pellet cores obtained in step c, and dried;

(ii) Preparation of second pellets

a, by taking the ratio of each raw material, viz, Lycopene with CLA

b, the components of the active-containing layer is configured to mix the said active containing layer coating solution, the active containing layer coating solution with the active, then granulated and dried;

c, the isolation layer packet, mixing the components of the separation layer is configured to release layer coating liquid, the coating liquid for release layer on the pellet cores obtained in step b, and dried;

d, enteric coated layer, matching Intestinal pH, the configuration of the components into the enteric coating layer of enteric coating solution, a coating solution for enteric coating on the pellet cores obtained in step c, and dried

(iii) Preparation of third pellets

a, by taking the ratio of each raw material, viz, Selenium

b, the components of the active-containing layer is configured to mix the active containing layer coating solution, the active containing layer coating solution with the drug, then granulated and dried;

c, the isolation layer packet, mixing the components of the separation layer is configured to release layer coating liquid, the coating liquid for release layer on the pellet cores obtained in step b, and dried;

d, enteric coated layer to match Colon pH, the configuration of the components into the enteric coating layer of enteric coating solution, a coating solution for enteric coating on the pellet cores obtained in step c, and dried

Pellets prepared with these steps of the same; (3) the first, second and third pellets are lubricated at a mass ratios mixed and filled into capsules.

The capsules are prepared with suitable auxiliaries to provide stability, enhanced solubility and release profile. In order to combat destruction by gastric acid, speed of onset and bioavailability problems, the capsule of the present invention, contains three pellets with three different coating layer and release agents in pellets. The agents used in the three release pellets can be dissolved at a specific pH environment, the first pellets at pH3.5 environment, the second is an exploded pellets at ambient pH from 7.0 to 7.6, and the third is the targeted release at ambient pH in colon. Accordingly, the present invention provides is controlled release capsules demonstrating release of the labeled amount avoiding Lycopene destruction in gastric acid, and delivered to the intestinal tract, and onset release rapidly so as to improving bioavailability.

Example IB: Evaluation of efficacy of the formulation a prepared above:

Formulation: Iodine 100 meg, Selenium 200 meg, Vitamin D31000IU, Lycopene5000 meg in unit dosage

Placebo: Placebo was made from the very same materials (excipients) as the active product except for the absence of active ingredient.

STUDY DESIGN AND PROCEDURE

The study was designed as a multi-center, observational, placebo controlled, prospective, two arms, parallel group study to evaluate the safety and efficacy of the present invention nutraceutical composition. The study was conducted at two Indian sites.

Procedure:

Informed consent was obtained from all the patients before enrolling in the study. The screening period was of 7 days. Eligible subjects were randomly assigned to one of the two study groups in 1 : 1 ratio.

- Group 1 : the present invention composition capsule once daily for 90 days.

- Group 2: Placebo once daily for 90 days.

The eligibility of the subject was confirmed based on their medical history. Eligible subjects then were randomized to either of the treatment arm. IP or Placebo was dispensed for 30 days at day 0, day 30, and at day 60 to the subjects. Follow up was conducted on Day 15 (EOS).

A total of 15 ml of venous blood sample was withdrawn at screening and on Day 6 (discharge) for hematological and biochemical parameters. Improvement in the platelet count was assessed at screening, on Day 3 and on Day 6.

Treatment groups:

Subjects were assigned to one of the two treatment arms in a 1 : 1 ratio based on randomization list. The treatment arms were as follows:

Number of Patients: A total of 200 patients were assigned to two treatment arms in 1 : 1 ratio.

Inclusion Criteria:

- Female subjects above 18 to 50 years of age and willing to give written inform consent

- Pregnant Women diagnosed with Hypothyroidism

- Newly diagnosed patients with subclinical hypothyroidism

- Diagnosed cases of hypothyroidism based on Serum TSH, T3 and T4 levels

- Patient Serum TSH level above 2.1 mU/L

Total Serum T4 level less than normal value (4.5 to 12.5 ng/dl).□ Total Serum T3 level less than normal value (80 to 220 ng/dl) Exclusion Criteria:

Subject with a history of smoking or currently taking any herbal preparations (such as other formulations containing Ashwagandha, ginseng, Brahmi, Ginkgobiloba) Ischemic heart diseases

- Uncontrolled hypertension

- Myocardial Infarction

Cerebrovascular event

- Cardiac arrhythmias

Active malignant disease

Study Design And Plan:

The study was designed as a multicenter, observational; two arm study, randomizing 200 patients. 100 patients in each arm to measure the efficacy, safety of present invention composition in two groups.

Duration of Treatment: Total duration of treatment was 90 days.

Study Background Rationale:

Imbalance in hormone released by thyroid gland during pregnancy may lead to various complications like preeclampsia, retarded brain development, placental abnormalities, preterm birth, Neurocognitive deficits etc. Therefore it is very important to address deficiency of Iodine and Selenium during pregnancy, along with Vitamin D3 and Lycopene. Together Iodine, selenium, Vitamin D3 and Lycopene not only control the functionality of Thyroid gland and its health but also ensure that complications can be taken care off. The present invention nutraceutical composition was provided in the form of capsules which are meant for oral use only which has been found to help in maintaining effective levels of T3, T4 and TSH.

Randomization and Blinding: Randomized placebo controlled clinical trial conducted

EXAMPLE 2: Statistical Analysis

General Considerations: Statistical Analysis Plan, Statistical Analysis was done based on study parameters by using SPSS software Version 20.0. Demographics and Baseline Characteristics: Demographic and baseline characteristics, including age, sex, race, weight, medical history and any other study- appropriate data, was tabulated and summarized.

Efficacy analysis: Efficacy analysis included normal levels of T3, T4 and TSH], (from randomization day 90) that were compared within and between groups.

The study included 220 pregnant women with 110 each in Treatment and Placebo arm. The TSH, as a key indicator of thyroid dysfunction, was measured at the beginning and after 90 days of treatment. The pretreatment TSH levels were obtained for all the women in both the groups. After 90 days, there were 6 and 8 cases of lost to follow up in Treatment and Placebo groups respectively.

The descriptive statistics for demographic, anthropometric and clinical parameters are given in Table 1 for all the patients included in the study.

Table 1

The mean age of women in Placebo group (25.91 ± 4.49 years) was insignificantly different than that of Treatment group (26.73 ± 5.02 years) as indicated by p-value of 0.2042. Further, the mean weight in Placebo group (55.47 ± 10.99 kg) was insignificantly different than that of Treatment group (54.35 ± 9.35 kg) with p-value of 0.3606. Both systolic and diastolic blood pressures were also insignificantly different in two groups, as indicated by their respective p-values > 0.05. In other words, women in both the groups were balanced as regards the baseline characteristics.

Figure 1 depicted column chart showing mean levels of each parameters in Placebo and Treatment group. EXAMPLE 2a- Statistical Analysis-Women with history of complications This example provides the number of women according to complications.

Table 2: Number of women with past history of complications

Table 2 gives the number of women according to complications. Out of 110 women in Placebo group, 8 (7.27%) had PCOS, while in Treatment group 15 (13.64%) had PCOS. Overall, 23 (10.45%) women had PCOS. There were 10 (9.09%) cases of PCOD in Placebo group, while 6 (5.45%) cases in Treatment group. Overall 16 (7.27%) cases had PCOD. In Placebo group, there were 3 (2.73%) cases of BOH, while in Treatment group, there were 5 (4.55%) cases of BOH. Overall, the proportion was 3.64%. Cases with single abortion were 3 (2.73%) in Placebo group, while 4 (3.64%) in Treatment group. The overall percent of abortion was 3.18%. Further, there were 3 (2.73%) cases of ovular distress in Placebo group, while 2 (1.82%) had such problem in Treatment group. The overall percent of ovular distress was 2.27%. Other complications were observed in less than 2% of the cases. Figure 2 depicted horizontal bar chart showing number of women with different complications EXAMPLE 2b: Statistical Analysis- Distribution of Patients according to diagnosis

This example provides the distribution of women according to diagnosis in Placebo and Treatment groups. Table 3: Number of women according to diagnosis in two groups

Table 3 provides the distribution of women according to diagnosis in Placebo and Treatment groups. There were 85 (77.27%) women with pregnancy induced hypertension (PUT) in Placebo

group, as against 99 (90%) in Treatment group. A total of 184 (83.64%) women had PUT. Sub-clinical hypothyroidism cases were 11 (10%) in Placebo, while 6 (5.45%) in Treatment group. Overall, there were 17 (7.73%) cases with this diagnosis. Further, hypothyroidism and infertility was observed in 9 (8.18%) cases in Placebo group, while 5 (4.55%) in Treatment group. Hyperthyroidism was observed in 4 (3.64%) cases in Placebo. One case of severe hypothyroidism was observed in Placebo group. Figure 3 depicted Pie chart showing distribution of women according to diagnosis.

EXAMPLE 2c: Statistical Analysis- Distribution of Patients according to diagnosis

Table 4: Distribution of women according to month of diagnosis of thyroid dysfunction in two groups

Table 4 gives the number of women according to the month of diagnosis of thyroid dysfunction in two study groups. Overall, 23 (10.45%) women were diagnosed with the problem in the first month. Placebo group had 14 (12.73%) of the cases, while Treatment group had 9 (8.18%) cases. There were 38 (34.55%) cases in Placebo group diagnosed at second month, while 53 (48.18%) cases were diagnosed in Treatment group at second month. There were 37 (33.64%) and 35 (31.85%) cases diagnosed at third month in Placebo and Treatment groups respectively. Figure 4 depicted pie chart showing distribution of women according to month of diagnosis.

EXAMPLE 2d: Statistical Analysis- Descriptive statistics for TSH in two study groups

This example illustrates the comparison of TSH levels before and after 90 days in both the study groups.

Table 5: Descriptive statistics for TSH at pre and post time points in two study groups

*Using paired t-test; {Using t-test for independent samples; **Excluding hyperthyroidism cases Table 5 gives the comparison of TSH levels before and after 90 days in both the study groups. The analysis was performed on samples with both pre and post TSH levels recorded. There were 102 cases in Placebo and 104 in Treatment group with TSH levels recorded at both instances. In Placebo group, the mean pre-treatment TSH level was 5.13 ± 2.87 mU/L, while the post-treatment mean level was 2.37 ±1.04 mU/L. The change in the mean level after 90 days was statistically significant with p-value < 0.0001. Similarly, in treatment group, the mean pre-treatment level was 5.81 ± 3.71 mU/L, while the post treatment mean was 2.05 ± 1.16 mU/L and the change in the means was statistically significant with p- value < 0.0001. The comparison of pre-treatment TSH means between two groups revealed that the difference was statistically insignificant (p = 0.1423). In other words, the initial mean TSH levels in two groups were statistically similar. However, the post-treatment difference of means between two groups was significant as indicated by p-value of 0.0351. The mean after 90 days in Treatment group was significantly lower than that of Placebo group.

The mean percent reduction of TSH level in Placebo group was 52.0 ± 16.98, while that of Treatment group was 60.5 ± 16.24. The mean reduction was significantly higher in Treatment group as compared to Placebo group (p=0.0008). All the subjects attained normal TSH values after 90 days. Figure 5 depicted Column chart with error bars showing mean TSH levels in two study groups at pre and post times.

EXAMPLE 3: Comparative testing Results

Table 6A: Comparison of pre and post-treatment TSH levels as per diagnosis in two groups as well as between groups.

*Using paired t-test; 'Using t-test for independent samples

Table 6 gives the comparison of pre and post treatment TSH levels in Placebo and Treatment groups, according to diagnosis. In Placebo group, in hyperthyroidism category, the mean TSH level increased significantly from pre state (0.22 ± 0.23 mU/L) to post state (3.03 ± 0.63 mU/L) with a p-value of 0.0053. For patients with hypothyroidism and infertility, in Placebo group, the mean TSH level at pre state (3.68 ± 2.35 mU/L) significantly reduced to 1.93 ± 1.46 mU/L at post state (p = 0.0324). Similar was the observation in Treatment group. The mean pre state level (3.90 ± 1.29 mU/L) significantly reduced to 2.10 ± 1.43 mU/L at post state (p = 0.035). However, the difference of means between two groups at pre and post states were statistically insignificant as indicated by p-values 0.8694 and 0.8814 respectively.

On the other hand for pregnancy induced hypothyroidism, in Placebo group, the mean at pre state (5.84 ± 2.66 mU/L) reduced significantly at the post state (2.49 ± 1.03 mU/L) with a p-value < 0.0001. In Treatment group also, the mean at pre state (6.02 ± 3.74 mU/L) reduced significantly at post state (2.08 ± 1.17 mU/L) with a p- value < 0.0001. The difference of mean TSH levels at pre state between two groups was statistically insignificant (p=0.7149), while post state difference between two groups was statistically significant (p=0.0146). In

other words, the mean TSH levels at post state in Treatment group was significantly lower as compared to that of Placebo group.

Further, in patients diagnosed with sub-clinical hypothyroidism, in Placebo group, the mean TSH levels at pre state (2.19 ± 0.12 mU/L) reduced significantly to a mean of 1.43 ± 0.37 mU/L at post state (p < 0.0001). In the Treatment group, the mean pre state level (2.13 ± 0.15 mU/L) reduced significantly at post state (1.23 ±

0.10 mU/L) with p-value of 0.0016. The between group comparison of mean TSH levels at pre and post states revealed that the differences were statistically insignificant with p-values 0.5031 and 0.1513 respectively. Figure 6 depicted column chart showing mean TSH levels in two study groups at pre and post times according to diagnosis.

The comparison of mean percent reduction in TSH levels between two groups was determined according to diagnosis.

Table 6B: Comparison of percent reduction in TSH levels as per diagnosis between two groups

*Using t-test for independent samples

The comparison of mean percent reduction in TSH levels between two groups was determined according to diagnosis.

5 In Hypothyroidism and infertility category, the mean reduction in Placebo group was 49.8 ± 9.73, while that in Treatment group was 50.10 ± 20.35, and the difference was statistically insignificant (p= 0.9816). However, in PIH category, the mean percent reduction in Placebo group (54.5 ±

16.41) was significantly lower than that of Treatment group (61.0 ± 16.30), as indicated 10 by p-v alue of 0.0024. In sub- clinical category, the mean reduction in Placebo group was 36.4 ± 14.07, while that in Treatment group was 42.2 ± 5.57, and the difference was statistically insignificant (p= 0.2785).

Table 7: Number of adverse events in two groups

No adverse event was observed in either of the groups.

15 Results

The study included 110 mothers diagnosed with thyroid disorder during first trimester as well as 1 10 mothers with normal TSH levels at the first trimester. Majority of the mothers had pregnancy induced hypothyroidism (PIH) with a mean pre-treatment TSH level reducing significantly after treatment. Similar was the observation in cases with 20 hypothyroidism and infertility and sub-clinical hypothyroidism. In other words, the normal TSH levels were attained following the treatment by the third trimester in 159 out of 172 cases (92.44%). Thus, irrespective of the presence or absence of thyroid disorder during pregnancy, the treatment helps in attaining or retaining the TSH levels during pregnancy, thereby minimizing the risk of complications due to thyroid disorders.

Although the present invention has been described in considerable detail with reference to certain preferred embodiments thereof, other versions are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description and the preferred versions contain within this specification.

The above results clearly go to establish that the treatment with the present composition though has less amount of iodine than recommended doses and has selenium, Vitamin D3 and lycopene which were not all known to act together specially to reduce pregnancy induced hypothyroidism, have achieved the same and that too to a significant level.

Conclusion

The double blinded randomized controlled two arm study with one group treated with the present invention composition and the other with placebo, in addition to the standard of care treatment demonstrated that.

- Each group had 110 women and the baseline parameters like age, weight and blood pressure were insignificantly different between groups.

- Majority of the women in either group were without any history of complications.

In both the groups, the cases of pregnancy induced hypothyroidism were predominant, followed by sub-clinical hypothyroidism.

- For majority of the women, the treatment initiated in 2nd or 3rd month of gestation in both the groups.

The mean TSH levels before treatment were insignificantly different between groups. After 90 days, the mean TSH levels were significantly reduced in both the groups. After 90 days, the mean TSH level in treatment group was significantly smaller than that of placebo group.

The percent reduction in TSH level in treatment group was significantly higher than that of placebo group.

This is particularly important since such composition with iodine, selenium, vitamin D3 and lycopene provided unexpected effect in controlling pregnancy induced

hypoythyroidism which has hitherto not been shown earlier.