WO2019226349A1

WO2019226349A1 - Oral composition of citrus pectin and papain to decrease plasma free igf-1 levels in individuals who need it and methods of preparation in soft capsule and syrup dosage forms

Info

Publication number: WO2019226349A1
Application number: PCT/US2019/031326
Authority: WO
Inventors: Mauricio DOBBOLETTA
Original assignee: Brix Usa Llc
Priority date: 2018-05-22
Filing date: 2019-05-08
Publication date: 2019-11-28
Also published as: AR112188A1

Abstract

An oral composition based on pectin and papain to reduce the levels of free IGF-1 in plasma of individuals who need it, such composition includes pectin of at least 65% of D-galacturonic acid and papain with a proteolytic activity of at least 6,000 U/mg, where pectin and papain have an effective weight ratio of approximately 250:3, respectively, and are moistened by means of at least two C_3-6 polyols, being the pH of the composition in the order of 6 obtained with the addition of at least one C_2-6alkanolamide, and also comprising emulsifiers, preservatives, and pharmaceutically acceptable solvents. Methods to prepare this oral composition as a soft capsule and as a syrup. A method to reduce the levels of free IGF-1 in plasma of individuals who need it with such oral composition, which comprises administering such individuals a dosage comprising at least about 250 mg of pectin and at least about 3 mg of papain every at least 12 hours for at least 28 days. The plasma transport protein IGFBP-3 levels are thereby increased which, when binds to IGF-1, forms a ternary complex with a labile subunit whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life decreasing the levels of free IGF-1. The use of pectin and papain together to prepare such oral composition.

Description

ORAL COMPOSITION OF CITRUS PECTIN AND PAPAIN TO DECREASE PLASMA FREE IGF-1 LEVELS IN INDIVIDUALS WHO NEED IT AND METHODS OF PREPARATION IN SOFT CAPSULE AND SYRUP DOSAGE FORMS

SPECIFICATION

FIELD OF THE INVENTION

This invention belongs to the field of compositions that decrease the levels of insulin like growth factor IGF-1 , which is a leading factor for malignant neoplasms, diabetes, neuropsychiatric disorders and cardiovascular diseases, it is more particularly related to oral compositions that combine pectin and papain to increase plasma levels of transport protein IGFBP-3, binding and sequestering IGF-1 , forming a complex whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life decreasing plasma free IGF-1 levels.

DESCRIPTION OF THE PREVIOUS ART IGF-1 and malignant neoplasm

According to WHO (World Health Organization), malignancy or cancer is one of the leading causes of morbidity and mortality in the world. Around 14 million new cases were registered in 2012. The number of new cases is expected to increase by approximately 70 per cent over the next 20 years. Cancer is the second leading cause of death in the world; in 2015, it caused 8.8 million deaths. Almost one in six deaths in the world is due to this disease.

The origin of cancer lies in the process of stem cell division, so the greater the number of divisions these cells accumulate, the greater the risk of developing this disease. DNA is the only cellular component capable of accumulating damage throughout its life, causing such damage during the process of cell division. It is during division that cells expose their DNA to certain carcinogens, so that alternations can occur that affect DNA structure.

The only cells capable of maintaining and transmitting DNA from zygote cells to the formation of a possible cancer are stem cells. The rest of the cells receive DNA from stem cells, but DNA is lost when the cells are replaced by new ones. At any given time, alterations in the DNA of stem cells can lead to the occurrence of cancer cells and, in addition, these stem cells may become cancer stem cells, which are already capable of initiating tumor growth on their own.

The role of insulin growth factor type 1 (IGF-1 , Insulin-like Growth Factor 1) in this process is to stimulate the division of stem cells, as IGF-1 is the main mediator of the effects of growth hormone. This is why this factor favors the accumulation of DNA damage, which can lead to the occurrence of cancer cells and the transformation of normal stem cells into cancer stem cells. In addition, once cancer stem cells have developed, this factor also stimulates their division, favoring the development of tumors. Therefore, we can come to the following conclusion: IGF-1 is an important leading factor for neoplasms.

Insulin-like growth factors (IGFs) are mitogens that play a key role in regulating cell proliferation, differentiation, and apoptosis. The effects of IGFs are mediated through the IGF-1 receptor, which is also involved in cell transformation induced by proteins from tumor viruses and oncogene products. Six IGF-binding proteins (IGFBP, Insulin-like Growth Factor Binding Protein) can inhibit or improve the actions of IGFs. These opposite effects are determined by the structures of the binding proteins. Laboratory studies have shown that IGFs exert strong mitogenic and antiapoptotic actions on various cancer cells. IGFs also act synergistically with other mitogenic growth factors and steroids by antagonizing the effect of antiproliferative molecules on cancer growth. The role of IGFs in cancer is supported by epidemiological studies that have found that high levels of circulating or free IGF-1 and low levels of IGFBP-3 are associated with the further development of several common cancers, including prostate, breast, colon, and lung cancer.

Evidence suggests that certain lifestyles, such as a high energy diet, may increase IGF-1 levels, a finding supported by animal experiments indicating that IGFs may eliminate the inhibitory effect of energy restriction on cancer growth. Therefore, knowing the role of IGFs in connection with high energy intake, increased cell proliferation, suppression of apoptosis, and cancer generation can provide new insights into the etiology of cancer and lead to new strategies for cancer prevention and treatment.

IGF-1 and diabetes

According to the WFIO (World Health Organization) the number of individuals with diabetes has increased from 108 million in 1980 to 422 million in 2014. The global prevalence of diabetes in adults (over 18 years) has increased from 4.7% in 1980 to 8.5% in 2014.

Diabetes is a major cause of blindness, kidney failure, myocardial infarction, stroke, and amputation of the lower limbs. It is estimated that diabetes was the direct cause of 1.6 million deaths in 2015. Another 2.2 million deaths were attributable to hyperglycemia in 2012.

Approximately half of deaths attributable to hyperglycemia occur before age 70 years. According to WFIO projections, diabetes will be the seventh leading cause of death in 2030.

Although diabetes is a heterogeneous condition, IGF-1 has been shown to improve glycemic control and reduce insulin requirements in both IDDM ( Insulin-Dependent Diabetes Mellitus) and NIDDM ( Non-Insulin-Dependent Diabetes Mellitus).

In IDDM, the therapeutic reason for IGF-1 is as a replacement therapy that “complements” the low levels of circulating IGF-1. There is now convincing evidence that this is associated with a reduction in GFI ( Growth Hormone) secretion resulting in improved insulin sensitivity and glycemic control. IGF-1 , predominantly synthesized in the liver after stimulation by GH, generally binds to circulating binding protein IGFBP-3. IGF-1 has a homology of almost 50% with the amino acid sequence of insulin and causes almost the same hypoglycemic response. The effect of IGF-1 on insulin sensitivity and its relationship to type 2 diabetes has been investigated. The increased risk of insulin resistance, metabolic syndrome, and type 2 diabetes is known in subjects with low serum concentrations of IGF-1 or low IGF-1 /IGFBP-3 ratio. Flowever, a German study of 7,665 subjects showed that both low and high serum concentrations of IGF-1 were associated with an increased risk of developing type 2 diabetes in 5 years. This U-shaped association appears to be likely in the face of a higher prevalence of metabolic syndrome or type 2 diabetes in patients with GFI deficiency, a state of low IGF-1 levels, as well as high IGF-1 levels. Both low and high normal levels of IGF-1 are associated with insulin resistance, a U-shaped relationship between IGF-1 levels and insulin sensitivity as a precursor to overt type 2 diabetes.

IGF-1 and neuropsvchiatric disorders (depression, anxiety, post-traumatic stress and neurodeqenerative disorders).

Currently, about 450 million individuals are affected by a mental or behavioral disorder. According to the WFIO Global Burden of Disease 2001 , 33% of the years lived with disability are caused by neuropsychiatric disorders. Depressive disorder alone causes 12.15% of years lived with disability and is the third contributing cause to the overall burden of disease.

There is a relationship between insulin growth factor type 1 IGF-1 and neuropsychiatric disorders such as autism, anxiety, depression, Alzheimer’s disease, and post-traumatic stress disorder.

In conclusion, insulin growth factor type 1 IGF-1 is an important neurotrophic factor, whose regulatory network operates throughout the body. Many of its recognized functions in the development of the nervous system have multiple neurotrophic, metabolic, cell growth, and neuroprotective properties. However, the role of IGF-1 in neuropsychiatric disorders, which yield contradictory data on highly prevalent disorders such as those affecting mood, is not fully understood.

In reference to its relationship with depression, the role of IGF-1 in the control and regulation of mood has been suggested due to its implication in processes such as synaptic plasticity, cell differentiation, and neurogenesis.

It is possible that these contradictory results are due to several factors not yet explored, such as the implication of several super families of insulin-like growth factor binding proteins in depression, as well as mechanisms of resistance to insulin growth factor type 1 IGF-1 involved.

Regarding anxiety, animal studies show that reduced levels of circulating or free insulin growth factor type 1 IGF-1 are associated with a greater presence of anxious symptoms and less neurogenesis in the hippocampus.

Experimental studies show important relationships between altered mechanisms of insulin growth factor type 1 IGF-1 , e.g. insulin growth factor type 1 receptor IGF-1 R (Insulin-like Growth Factor-1 Receptor), substrate of insulin receptor type 1 , AKT (or protein kinase B), phosphatidyl inositol-3-kinase and others, with symptoms of post- traumatic stress disorder, anxiety and depressive symptoms in animals; as well as structural alterations of the hippocampus, prefrontal cortex, amygdala, and hypothalamus. The latter would be particularly relevant as it would be the starting point of the growth hormone/insulin growth factor type 1 axis, or of the hypothalamic- pituitary-adrenal axis. This last axis mediates the response to stress. At the same time, glucocorticoids appear to be associated with alteration of the insulin growth factor type 1 intracellular signalling pathway, affecting, e.g., neurogenesis and leading to atrophy in the hippocampus.

However, greater implications have been found in neurodegenerative disorders. With regard to Alzheimer’s disease, it has come to be known as“type III diabetes” due to its high relationship with the mechanisms of type 2 diabetes, the etiological hypothesis of resistance to peptides such as insulin and insulin growth factor type 1 IGF-1 , as well as its experimental treatment with these peptides.

The implication of insulin growth factor type 1 IGF-1 in brain maturation, synaptogenesis, brain plasticity, neurogenesis, memory, and learning; as well as its antiapoptotic and neuroprotection mechanisms, makes it a potential therapeutic resource for neuropsychiatric disorders affecting such conditions.

IGF-1 and cardiovascular diseases (CVD)

Cardiovascular diseases are the leading cause of death worldwide. More individuals die each year from cardiovascular diseases than from any other cause. An estimated 17.5 million individuals died from this cause in 2012, accounting for 31 % of all recorded deaths worldwide. Of these deaths, 7.4 million were due to coronary heart disease and 6.7 million to strokes. More than three-quarters of CVD deaths occur in low- and middle-income countries. Of the 16 million deaths of individuals under 70 years old attributable to non-communicable diseases, 82% are in low- and middle- income countries and 37% are due to cardiovascular diseases, according to WFIO data from January 2015.

Vasculoprotective effects described for IGF-1 : local and systemic vasodilation (physiological effect); inhibition of adherence of human peripheral blood monocytes to endothelial cells {in vitro effect); and reduction of triglycerides and LDL {Low Density Lipoprotein) cholesterol (physiological effect).

In the same sense, it has been observed that there is an inverse correlation between the severity of hypertension and the serum level of that mediator. In favor of a cause/effect relationship between IGF-1 and cardio-metabolic risk, it has been shown that the risk for developing type 2 diabetes or myocardial infarction is significantly lower in carriers of genetic polymorphism in the IGF-1 promoting region with increased serum expression of that mediator. This finding reveals the protective effects of chronic exposure to elevated levels of IGF-1. Similarly, another case/control investigation showed that IGF-1 levels were lower in subjects with ischemic heart disease than in subjects without it. Low levels of IGFBP-3 were associated with coronary risk.

IGF-1 and IGF-1 lowering drugs

In order to reduce the levels of free IGF-1 , from a pharmacological point of view, there are several options that interfere with the activation axis for this factor.

The drugs octreotide and lanreotide are used in the treatment of acromegaly as analogues of somatostatin, so that they inhibit the release of growth hormone over a long period of time. Both drugs have been used in cases of secondary acromegaly in tumors, such as pituitary adenoma, but have also been shown to be effective in the treatment of non-endocrine tumors.

There is a study that evaluates tumor shrinkage and GFI and IGF-1 levels after a 3- month treatment with these drugs, where it was analyzed whether these levels could predict tumor shrinkage after a 12-month treatment. The result was that the percentage shrinkage of the tumor after 12 months of treatment correlated significantly with GFI and IGF-1 levels and that, therefore, shrinkage of tumor size could be predicted.

The side effects of the octreotide may be serious: pain in the upper right stomach, center of the stomach, back, or shoulder; yellowing of the skin or eyes; slow or irregular heartbeat; tiredness; sensitivity to cold; pale and dry skin; brittle nails and hair; swollen face; hoarse voice; depression; heavy menstrual periods; swelling at the base of the neck; throat tightness; difficulty breathing and swallowing; rash; and itching. The side effects of lanreotide are: allergic reaction; itching or hives; swelling of the face or hands; swelling or tingling in the mouth or throat; chest tightness; difficulty breathing; increased thirst, appetite, or urine; severe stomach pain with nausea and vomiting; yellowing of the skin or eyes; tremor; sweating; hard or fast heart rate; fainting; confusion; slow heartbeat; difficulty breathing; bleeding; bruising; or unusual weakness.

The somatostatin receptors are associated with a G protein that regulates their actions, so that binding to octreotide or lanreotide produces direct effects, such as the activation of apoptosis, and indirect effects such as the suppression of growth factors or precursor hormones thereof. Thus, a treatment with somatostatin analogues for 5 years produced a tumor reduction of 76%, as solid tumors express receptors for somatostatin on their surfaces. It is for this reason that there are currently new alternatives under development, such as pasireotide, which binds these receptors with greater affinity, highlighting the importance of taking action at this level when treating cancer.

Another alternative studied is pegvisomant, a GH receptor antagonist used in acromegaly when other alternatives, such as surgery or radiation, do not work well. This drug blocks the action of growth hormone at the receptor level, preventing the release of IGF-1. A study has shown that the effect of pegvisomant in breast cancer patients resulted in a 60% suppression in IGF-1 mRNA levels at the hepatic level, and a 70-80% reduction in their serum levels. This effect was mediated by a complete inhibition of the GFI and IGF-1 receptors, demonstrating that this activation axis plays a fundamental role in the development of the mammary gland. With all this, pegvisomant is useful for the prevention and treatment of estrogen-dependent breast cancer. Thus, blocking IGF-1 lowers estrogen levels and reduces the risk of breast cancer.

The side effects of pegvisomant are: thickening of the skin or a hard lump where the drug is injected, easy bruising, liver disorders with nausea, pain in the upper part of the stomach, itching, feeling tired, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes), pain; fever, chills, body aches, flu symptoms, nausea, diarrhea, abnormal liver function tests, and pain or irritation where the injection was given.

IGF-1 is not only released by activation of the adenohypophysis and subsequent stimulation of growth hormone in the liver. As mentioned earlier, insulin promotes the release of this factor at the liver level as a result of glucose intake. In this way, we have another alternative to reduce IGF-1 production: metformin. The use of metformin, the most common drug in treating type 2 diabetes, has been associated with a lower risk of certain types of cancer. This action is associated with the inhibition of the protein complex mTOR ( mammalian Target Of Rapamycin), which plays a crucial role in the metabolism, growth and proliferation of cancer. Glucose excessive intake or a diet rich in glucose results in increased hepatic production of IGF-1 , which binds to its receptor and to insulin receptor. After this, PI3K (phosphoinositol 3-kinase) and AKT (or protein kinase B) are activated, which indirectly trigger mTOR and Ras/Raf/MAPK ( Rat sarcoma/Rapidly Accelerated Fibrosarcoma/Mitogen-Activated Protein Kinase), leading to cell growth. In addition, a trial in non-diabetic women with breast cancer in which metformin was tested not only resulted in a small number of cancer cells, but also produced a series of changes in the expression of molecules related to the activation axes of mTOR and MAPK ( Mitogen-Activated Protein Kinase). Thus, it has been suggested that metformin has a dual action, because on the one hand it reduces insulin levels, which stimulate the release of IGF-1 , and on the other it inhibits mTOR. Biguadines have thus been shown to be useful in treating cancer.

Side effects of metformin include: diarrhea, bloating, stomach pain, flatulence, indigestion, constipation, unpleasant metallic taste in the mouth, heartburn, headache, skin redness, nail changes, and muscle pain.

In addition to insulin, there are other pathways by which IGF-1 is released: mesenchymal stem cells and macrophages. As we said, mesenchymal cells are stimulated by factors such as TNF-a {Tumor Necrosis Factor-a ), lipopolysaccharides or hypoxia, so that a release of IGF-1 takes place. This could be framed within the paracrine function of IGF-1 as these factors are characteristic of inflammation processes, so that in response to multiple damage mesenchymal cells increase the secretion of IGF-1.

Another important source of this factor are macrophages, which release IGF-1 into muscle lesions when stimulated by TNF-a and lipopolysaccharides. These two factors together with hypoxia are characteristic of a tumor environment, so acting at this level may be a good alternative to reduce IGF-1 levels. If this factor can be produced by these cells in a paracrine manner, it would be a good idea to act on mesenchymal cells and macrophages, as IGF-1 is a necessary factor for tissue growth and differentiation, but, as mentioned above, an excess can lead to overstimulation of stem cell division resulting in the occurrence of cancer stem cells. Despite this, acting at the level of macrophages and mesenchymal cells remains an alternative under study as there are no conclusive results.

Flowever, we must point out that there are already drugs whose function is to interfere with the activation axis of IGF-1 and which act at the receptor level: blocking antibodies. In this group we have allosteric or non-competitive inhibitors of IGF-1 and competitive blockers of IGF-1. Allosteric inhibition results in a conformational change that reduces ligand binding and activation of tyrosine kinase activity in the beta subunit. Competitive inhibitors bind directly to the IGF-1 binding site and reduce the binding to very low levels. Many of these antibodies have the additional property of stimulating the internalization of receptors, resulting in an even greater response. Flowever, the duration of these effects and tumor response are not well characterized. The binding capacity of an antibody is directly related to the expression of IGF-1 receptors in tumor cells, so the problem is to find out the degree of expression of these receptors in the tumor and to establish how the prognosis of this tumor varies according to the number of receptors expressed on its surface.

That is why the main disadvantage of these drugs is their toxicity. IGF-1 has properties similar to insulin and its deregulation leads to insulin resistance, where multiple hyperglycemic conditions occur. In addition, GFI levels are higher in the inhibition of insulin factor because the negative feedback of IGF-1 is decreased, which increases the secretion of GFI whose effects are contrary to insulin. As a result, IGF-1 R ( Insulin-like Growth Factor-1 Receptor) blocking antibodies result in hyperglycemia, hyperinsulinemia, and high GFI levels. This fact, paradoxically, contributes to the proliferation of tumor cells by various mechanisms: 1 ) the hyperglycemic event can intracellularly activate the signaling axis, regardless of whether phosphorylation of the IGF-1 receptor takes place; 2) blockers of this receptor increase glucose levels, and this results in an event of hyperglycemia and tumor growth by stimulating the hybrid insulin receptor type A, which is activated by IGF-2 due to inhibition of IGF-1 R; and 3) GFI receptors are increased in some cancers and GFI stimulates tumor growth, regardless of the presence of IGF-1.

In addition to the above, when antibodies are used as therapy, the formation of complexes between soluble receptors of IGF-1 R and antibodies that are directed against this receptor is observed, reducing the amount of antibodies that interact with receptors on the surface of cancer cells. As a consequence, the formed complexes move IGF-1 and IGF-2 from circulation by binding them to soluble receptors, thereby increasing the amount of free IGF-1 and IGF-2 that can leave circulation and stimulate the receptors in the surface of cancer cells.

As a conclusion, the use of drugs such as these antibodies is the main disadvantage for selectivity because it is limited for cancer cells, so that normal cells are attacked and many toxic effects are produced.

Once the possible courses of action with respect to IGF-1 axis have been analyzed, the actions of IGF-1 that derive from the activation of its receptor will be studied, where a protein that plays a fundamental role stands out. This is the case with mTOR, so its inhibition is very important in reducing the effects of this insulin factor. For this, rapamycin or sirolimus, a macrolide type immunosuppressant medication used to prevent rejection of transplanted organs is used. Rapamycin inhibits the mTOR signaling pathways, thus preventing tumor cell proliferation, inducing tumor apoptosis, and suppressing tumor angiogenesis, making it effective in combating some cancers.

Side effects of rapamycin include: stomach pain; headache; constipation; diarrhea; nausea; joint pain; unusual bleeding or bruising; cough; swollen red and/or cracked throat; scaly skin; rash; skin rash; itching; difficulty breathing or swallowing; swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or legs; and hoarseness. With rapamycin, all the possible existing pharmacological alternatives that interfere with IGF-1 have been analyzed. Flowever, the use of drugs that decrease the levels of insulin-like growth factor IGF-1 is an important risk factor for neoplasms since the vast majority of them carry many toxic effects due to their lack of selectivity. It is therefore highly desirable to achieve the reduction of levels of insulin-like growth factor IGF-1 , which is considered a factor in the generation of neoplasms, diabetes, neuropsychiatric disorders, and cardiovascular diseases by using a drug whose side effects are not harmful to individuals who need it, since treating the development of a disease with significant counterproductive effects is not considered a good strategy. There is a need, therefore, for an oral composition that can solve the current problems of the art, this is to increase the levels of the transport protein IGFBP-3 in plasma by binding to IGF-1 , forming a ternary complex with a labile subunit whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life decreasing the levels of free IGF-1 in plasma, being useful to treat malignant neoplasms, diabetes, neuropsychiatric disorders, and cardiovascular diseases.

SUMMARY OF THE INVENTION

It is, therefore, the object of the present invention an oral composition based on pectin and papain to diminish the levels of free IGF-1 in plasma of individuals who need it, where this composition includes pectin of at least 65% of D-galacturonic acid and papain with a proteolytic activity of at least 6,000 U/mg, where pectin and papain have an effective weight ratio of approximately 250:3, respectively, and are moistened by means of at least two C3-6 polyols, being the pH of the composition in the order of 6 obtained with the addition of at least one C2-6 alkanolamide, and also comprising emulsifiers, preservatives and pharmaceutically acceptable solvents. Preferably, C3-6 polyol is 1 ,2,3-propanetriol (glycerin), 1 ,2-propanediol (propylene glycol), 1 ,3-butanediol, 1 ,4-butanediol, 1 ,3-butenodiol, 2,3-butenediol, 2,2-dimethyl- 1 ,3-propanediol (neopentyl glycol), erythritol, sorbitol (70%), mannitol, a combination of any two of them.

More preferably, C3-6 polyol is a combination of 1 ,2-propanediol (propylene glycol) and sorbitol (70%).

Also preferably, the pectin is apple bagasse pectin or citrus pectin.

Even more preferably, the pectin used is citrus pectin.

Preferably also, C2-6 alkanolamine is selected from the group consisting of: monoethanolamine, diethanolamine, triethanolamine, and mixtures thereof.

More preferably also, C2-6 alkanolamine is triethanolamine.

Preferably still, the non-ionic emulsifier is selected from the group consisting of polyoxyethylene (8) stearate (E-430); polyoxyethylene (40) stearate (E-431 ); polyoxyethylene (20) (20 OE or ethoxylated with 20 oxyethylene groups) sorbitan monolaurate (also known as polysorbate 20, Tween 20 or E-432); polyoxyethylene (20) sorbitan monooleate (polysorbate 80, Tween 80 or E-433); polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40, Tween 40 or E-434); polyoxyethylene (20) sorbitan monostearate (polysorbate 60, Tween 60 or E-435); polyoxyethylene (20) sorbitan tristearate (polysorbate 65, Tween 65 or E-436); and mixtures thereof.

Even more preferably, the non-ionic emulsifier is polyoxyethylene (20) sorbitan monolaurate (Tween 20).

Preferably still, the preservative is selected from the group consisting of methylparaben, ethylparaben, propylparaben, and mixtures thereof.

Even more preferably, the preservative is a mixture of methylparaben and propylparaben.

Preferably, the composition is in a soft capsule dosage form.

Alternatively, the composition is in a syrup dosage form.

Preferably, the oral composition comprises citrus pectin between approximately 20.00% and approximately 35.00% w/w, papain (of at least 6,000 U/mg) between approximately 0.10% and approximately 1.00% w/w, propylene glycol between approximately 30.00% and approximately 55.00% w/w, triethanolamine (99%) between approximately 2.00% and approximately 4.00% w/w, polyoxyethylene sorbitan monolaurate with 20 OE (Tween 20) between approximately 1.00% and approximately 3.00% w/w, sorbitol (70%) between approximately 10.00% and approximately 20.00% w/w, methylparaben between approximately 0.05% and approximately 0.30% w/w, propylparaben between approximately 0.02% and approximately 0.20% w/w, and sterile water q.s. to 100% w/w.

More preferably, the oral composition comprises citrus pectin in the order of 25.00% w/w, papain (of at least 6,000 U/mg) in the order of 0.30% w/w, propylene glycol in the order of 40.00% w/w, triethanolamine (99%) in the order of 3.00% w/w, polyoxyethylene sorbitan monolaurate with 20 EO (Tween 20) in the order of 2.00% w/w, sorbitol (70%) in the order of 15%, methylparaben in the order of 0.10% w/w, propylparaben in the order of 0.05% w/w, and sterile water q.s. to 100% w/w.

Also preferably, the oral composition comprises citrus pectin between approximately 2.00% and approximately 10.00% w/w, papain (of at least 6,000 U/mg) between approximately 0.05% and approximately 0.50% w/w, propylene glycol between approximately 5.00% and approximately 15.00% w/w, triethanolamine (99%) between approximately 0.20% and approximately 1.00% w/w, polyoxyethylene sorbitan monolaurate with 20 OE (Tween 20) between approximately 0.20% and approximately 1.00% w/w, sorbitol (70%) between approximately 15.00% and approximately 30.00% w/w, vanilla essence between approximately 0.20% and approximately 0.50% w/w, methylparaben between approximately 0.05% and approximately 0.30% w/w, propylparaben between approximately 0.02% and approximately 0.20% w/w, and sterile water q.s. to 100% w/w.

More preferably, the oral composition comprises citrus pectin in the order of 5.00% w/w, papain (of at least 6,000 U/mg in the order of 0.06% w/w, propylene glycol in the order of 10.00% w/w, triethanolamine (99%) in the order of 0.80% w/w, polyoxyethylene sorbitan monolaurate with 20 OE (Tween 20) in the order of 0.40% w/w, sorbitol (70%) in the order of 20%, vanilla essence in the order of 0.35%, methylparaben in the order of 0.10% w/w, propylparaben in the order of 0.05% w/w, and sterile water q.s. to 100% w/w.

It is another object of the present invention, a method to prepare the oral composition in a dosage form of soft capsule, which comprises:

a) add under stirring at approximately 500 rpm at least one C3-6 polyol and disperse papain of at least 6,000 U/mg and at least one preservative;

(b) lower the stirring rate to approximately 300 rpm and add at least one non-ionic emulsifier, pectin, and then at least one C2-6 alkanolamine until the acidity of the pectin is neutralized and a dispersion at approximately pH = 6 is formed;

(c) add at least one other C3-6 polyol and finally complete with sterile water to full weight forming a stable gel; and

(d) encapsulate in soft capsules the stable gel obtained in step (c) above.

Preferably, such a method comprises:

a) add under stirring at approximately 500 rpm propylene glycol and disperse papain of at least 6,000 U/mg, methylparaben, and propylparaben;

(b) lower the stirring rate to approximately 300 rpm and add polyoxyethylene sorbitan monolaurate with 20 OE, then citrus pectin and then triethanolamine (99%) until the acidity of citrus pectin is neutralized and a dispersion at approximately pH = 6 is formed;

c) add sorbitol (70%) and complete with sterile water up to 100% w/w forming a stable gel; and

(d) encapsulate in soft capsules the stable gel obtained in step (c) above.

It is still another object of the present invention, a method to prepare the oral composition in a dosage form of syrup, which comprises:

a) add under stirring at approximately 400 rpm at least one C3-6 polyol and disperse papain of at least 6,000 U/mg and at least one preservative;

c) add then at least one other C3-6 polyol, essence and complete with sterile water up to 100% w/w forming a stable syrup; and

(d) fractionate the stable syrup from step (c) above into dark bottles.

Preferably, this method comprises:

a) add under stirring at approximately 400 rpm propylene glycol and disperse papain of at least 6,000 U/mg, methylparaben, and propylparaben;

(b) lower the stirring rate to approximately 300 rpm and add polyoxyethylene sorbitan monolaurate with 20 OE, citrus pectin and then triethanolamine (99%) until the acidity of citrus pectin is neutralized and a dispersion at approximately pH = 6 is formed;

c) then, add sorbitol (70%), vanilla essence and complete with sterile water up to 100% w/w forming a stable syrup; and

(d) fractionate the stable syrup obtained in step (c) above into dark glass or plastic bottles.

Preferably, stirring from step a) is performed at approximately 500 rpm.

Also preferably, stirring of steps b) and c) is performed at approximately 300 to approximately 350 rpm.

Preferably, stirring from step a) is performed at approximately 400 rpm.

Also preferably, stirring of steps b) and c) is performed at approximately 250 rpm to approximately 300 rpm.

It is still another object of the present invention, a method to diminish the levels of free IGF-1 in plasma of individuals who need it, using the oral composition as described above, that includes administering to such individuals a dosage comprising at least 250 mg of pectin and at least about 3 mg of papain every at least 12 hours during at least 28 days.

Preferably, the decrease in plasma free IGF-1 levels are within the range of approximately 50% to approximately 70%.

Also preferably, the pectin is apple bagasse pectin or citrus pectin.

Even more preferably, the pectin used is citrus pectin.

In addition, the method achieves increased levels of plasma transport protein IGFBP-3 which, when binds to IGF-1 , forms a ternary complex with a labile subunit whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life decreasing free IGF-1 levels.

Also preferably, plasma levels of transport protein IGFBP-3 are within the range of approximately 30% to approximately 60%. Still preferably, the at least about 250 mg of pectin and the at least about 3 mg of papain are in dosage forms of soft capsules or each approximately 5 ml_ of syrup. Preferably, the method to decrease the levels of free IGF-1 in plasma of individuals who need it to treat malignant neoplasms, diabetes, neuropsychiatric disorders, and cardiovascular disease using the oral composition described above, administering to such individuals a dosage comprising at least 250 mg of pectin and at least 3 mg of papain every 12 hours for at least 28 days.

It is also still another object of the present invention, the use of pectin and papain together to prepare an oral composition as described, useful to reduce the levels of free IGF-1 in plasma of individuals who need it, by administering to such individuals a dosage comprising at least 250 mg of pectin and at least about 3 mg of papain every at least 12 hours for at least 28 days.

Preferably, in such use the decrease in plasma free IGF-1 levels are within the range of approximately 50% to approximately 70%.

Also preferably, the pectin is apple bagasse pectin or citrus pectin.

Even more preferably, the pectin used is citrus pectin.

In addition, the use as described above achieves increased levels of plasma transport protein IGFBP-3 which, when binds to IGF-1 , forms a ternary complex with a labile subunit whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life decreasing free IGF-1 levels.

Also preferably, in such use the increased levels of plasma transport protein IGFBP- 3 are within the range of approximately 30% to approximately 60%.

Still preferably, the at least about 250 mg of pectin and the at least about 3 mg of papain are in dosage forms of soft capsules or each approximately 5 ml_ of syrup. Even more preferably, the use includes treating malignant neoplasms, diabetes, neuropsychiatric disorders, and cardiovascular diseases using the oral composition, administering to such individuals a dosage comprising at least 250 mg of pectin and at least 3 mg of papain every 12 hours for at least 28 days.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 a shows the increase in plasma levels of IGFBP-3 during treatment with the oral composition in soft capsules from application example 1.

Figure 1 b shows the decrease in plasma levels of IGF-1 during treatment with the oral composition in soft capsules from application example 1.

Figure 2a shows the increase in plasma levels of IGFBP-3 during treatment with the oral composition in syrup from application example 2.

Figure 2b shows the decrease in plasma IGF-1 levels during treatment with the oral composition in syrup from application example 2.

Figure 3a shows the increase in plasma levels of IGFBP-3 during treatment with the oral composition in syrup from application example 3.

Figure 3b shows the decrease in plasma IGF-1 levels during treatment with the oral composition in syrup from application example 3.

Figure 4a shows the decrease in blood glucose levels during treatment with the oral composition in syrup in application example 4.

Figure 4b shows the decrease in plasma levels of IGF-1 during treatment with the oral composition in syrup from application example 4.

Figure 5a shows the decrease in plasma levels of CEA during treatment with the oral composition in syrup from application example 5.

Figure 5b shows the decrease in plasma levels of IGF-1 during treatment with the oral composition in syrup from application example 5.

DETAILED DESCRIPTION OF THE INVENTION

For the purpose of making the description of the invention clearer, the terms “approximately”,“in the order of”,“about”, or similar used throughout the specification mean that the numerical values affected are close to the limit value that is specifically mentioned and within a given range of values between more and less 20% of said numerical value, preferably between more and less 10% of such value and, more preferably, between more and less 5% of such value. The ranges are determined by the measurement method used and the confidence limits used in the corresponding determinations.

Both papain and pectins used are pharmacopoeial grade, e.g. USP ( United States Pharmacopeia), or food grade.

To overcome the drawbacks of prior art, an oral composition consisting of pectin and papain is proposed to increase plasma levels of transport protein IGFBP-3 by binding and sequestering IGF-1 , forming a complex whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life decreasing plasma free IGF-1 levels in individuals who need it, to treat malignant neoplasms, diabetes, neuropsychiatric disorders, and cardiovascular diseases.

The oral composition according to the present invention comprises a complex polysaccharide and a proteolytic enzyme, obtaining excellent results through its administration.

Pectin is a complex polysaccharide present in the cell wall of terrestrial plants. The word“pectin” comes from the Greek word for coagulated or curdled. Pectin from plants is used as a gelling agent in food processing and also in the formulation of drugs for oral and topical consumption as a stabilizing matrix that is not biodegradable and that supports the controlled administration of a drug.

Pectin is found, e.g., in the peel and pulp of citrus fruits and can be modified by treatment with high temperature and pH.

The modification produces shorter molecules that dissolve better in water and are more easily absorbed by the body compared to longer chain complex pectins.

One of the molecular targets of modified pectin is galectin-3, a protein found on the surface and inside mammalian cells and involved in multiple cellular processes such as adhesion, activation, chemo-attraction, cell multiplication, and differentiation, as well as cell cycle and apoptosis. Modified pectin inhibits the activity of galectin-3. Modified pectin may protect against several types of cancer, including colon, lung, and prostate cancer. Modified pectin may exert anticancer effects by interfering with tumor cell metastases or by inducing apoptosis.

Modified pectin was also observed to activate natural cytolytic lymphocytes in leukemic cell cultures, indicating that modified pectin may stimulate the immune system.

In a 2007 study, the anti-cancer properties of pectins were investigated. Prostate cancer cells were treated with three different pectins: citrus pectins, Pectasol (PeS, a dietary supplement with modified citrus pectin), and a fractionated pectin powder. Fractionated pectin induced a much higher degree of apoptosis than both citrus pectin and PeS. Further analysis found that treatment with hot citrus pectin in prostate cancer cells produced degrees of apoptosis similar to those following treatment with fractionated pectin. This indicates that the specific structural characteristics of pectin may explain its ability to induce apoptosis in prostate cancer cells.

In a 2010 study, prostate cancer cells were treated with PeS or PectaSol-C, the only two types of modified citrus pectin used in previous human studies. The investigators postulated that due to the low molecular weight of PectaSol-C, the bioavailability of PectaSol-C may be better than that of PeS. Both types of modified citrus pectin were evaluated at concentrations of 1 mg/mL and both were effective in inhibiting cell multiplication and inducing apoptosis by blocking the MAPK/ERK ( Mitogen-Activated Protein Kinase/Extracellular signal-Regulated Kinase) signaling pathway and by activating the enzyme caspase-3.

In one study, the role of galectin-3, a multifunctional endogenous lectin, in cisplatin- treated prostate cancer cells was investigated. Prostate cancer cells that expressed galectin-3 were resistant to the apoptotic effects of cisplatin. Flowever, cells that did not express galectin-3, due to the attenuation of galectin-3 expression by RNA (ribonucleic acid) interference or treatment with modified citrus pectin, were susceptible to cisplatin-induced apoptosis. These results indicate that galectin-3 expression may have a role in the chemoresistance of prostate cancer cells and that the efficacy of cisplatin treatment in prostate cancer could be improved by inhibiting galectin-3.

In a 2007 pilot study, patients with advanced solid tumors, representing various types of cancer such as prostate cancer, received modified citrus pectin at a dose of 5 g of modified citrus pectin powder dissolved in water 3 times per day for at least 8 weeks. After treatment, improvements were reported in some measures of quality of life, such as physical functioning, general health, fatigue, pain, and insomnia. In addition, after 8 weeks of treatment with modified citrus pectin, 22.5% of the participants had stable disease and 2.3% had stabilization of the disease that lasted more than 24 weeks.

In a 2003 study, the effects of modified citrus pectin on prostate-specific antigen (PSA) doubling time were investigated. Patients with prostate cancer with increasing PSA concentrations received 6 capsules of PeS 3 times daily in total doses of 14.4 g daily of modified citrus pectin powder for 12 months. After treatment, 7 out of 10 patients had a statistically significant increase (P < 0.05) in the PSADT.

Patent document W01996001640A1 (=ES2227555T3) discloses a modified citrus pectin drug for oral administration for the treatment of cancer, where modified citrus pectin binds to galectin-3 (Gal3), finding the disadvantage of side effects generated by modified citrus pectin. No reference is made to the decrease in plasma free IGF-1 levels.

Patent EP2661173B1 (=ES2613949T3) discloses a polyuronide that has the ability to bind to galectin 3 (Gal3) on the surface of cancer cells for use in a cancer- inhibiting method in a mammalian that needs it, comprising administering a synergistic amount of honokiol (HNK) and such polyuronide for a period of time long enough to inhibit such cancer, in which such polyuronide is a modified citrus pectin. The disadvantage of the side effects of the modified citrus pectin is found and the patent does not refer to the decrease in plasma free IGF-1 levels.

In a prospective pilot study, most patients tolerated the modified citrus pectin well. The most common side effects were pruritus, dyspepsia, and flatulence. In another study, no serious side effects of the modified citrus pectin were reported, although three patients discontinued the study due to intestinal cramps and diarrhea that improved once treatment ceased.

To overcome these drawbacks the present invention proposes the use of an unmodified pectin, which is normally used as a gelling agent in foods such as jams with no side effects observed, and to work on an oral composition without adverse effects to lower IGF-1 in individuals who need it.

Papain is a potent digestive enzyme frequently found in and extracted from the papaya fruit ( Carica papaya). Papain plays a fundamental role in the digestive process by participating in the decomposition of protein fibers.

The papaya enzyme, papain, can break down larger proteins into smaller proteins or peptides or even into smaller subunits of amino acids by segmenting the bonds within the protein chain or at the end of the chain, endopeptidase and exopeptidase activity, respectively, at a wide variety of pH values.

This gives papain a remarkable ability to improve the overall digestive process and increase the absorption of nutrients from protein-based foods. Papain ability to hydrolyze, i.e., break down, proteins also means that it can play an essential role in many normal physiological processes and may possibly have a positive influence on disease processes.

Papain may act as a support to the immune system, as proteolytic enzymes such as papain help modulate leukocytes in the immune response. Mice immunized with papain have serum antibodies that cross-react with endopeptidases like catepsin B and catepsin H isolated from melanoma cells B16. The growth rate, invasion and metastasis of both B16 melanoma and Lewis lung carcinoma were inhibited in mice immunized with papain. These animals had an increased mean survival time compared to non-immunized tumor-bearing controls. Quantitative microscopy suggested that vasodilation and edema, associated with tumor invasion, are at least partially sustained by proteolytic enzymes, being strongly reduced when tumor cells were inoculated into mice immunized with papain.

Papain retains compounds that can help protect the body from cell damage caused by free radicals.

In the present invention it is proposed to use the properties of pectin and papain on the decrease of IGF-1 as an important risk factor in malignant neoplasms, diabetes, neuropsychiatric disorders, and cardiovascular diseases, as well as in support of the immune system. Therefore, in the present invention, an oral composition combining pectin and papain is proposed to increase the levels of the transport protein IGFBP-3 in plasma. IGF-1 binds IGFBP-3 in a molar ratio of 1 :1 forming a ternary complex of 140,000 Dalton with IGF-1 and with a labile acid subunit reducing the levels of free IGF-1 in plasma in individuals who need it, overcoming the disadvantages of previous art.

The present invention shows in application examples 1 , 2, and 3 how increased levels of insulin-like transport protein IGFBP-3 in plasma bind in a molar ratio to free IGF-1 , forming a ternary complex with a labile subunit whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life decreasing plasma free IGF-1 levels in individuals who need it.

The present invention shows in application example 4 how increased levels of insulin-like transport protein IGFBP-3 in plasma bind in a molar ratio to free IGF-1 , forming a ternary complex with a labile subunit whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life decreasing free IGF-1 levels and decreasing levels of blood glucose and basal insulinemia in individuals with type 2 diabetes mellitus.

The present invention shows in application example 5 how increased levels of insulin-like transport protein IGFBP-3 in plasma bind in a molar ratio to free IGF-1 , forming a ternary complex with a labile subunit whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life decreasing free IGF-1 levels and reducing carcinoembryonic antigen (CEA) levels in individuals with colorectal malignancy.

The present invention has achieved a marvelously unexpected result as can be seen in comparative example 1 , where the efficacy of the combination of pectin and papain is widely superior to the efficacy of modified-pectin in lowering plasma IGF-1 levels.

In example 3 it can be seen what is the effective ratio of pectin and papain, this ratio is 250:3, respectively. This ratio applies to the two presentations, soft capsules and syrup.

A preferred embodiment of the present invention is an oral composition of pectin and papain to increase the levels of the transport protein IGFBP-3 in plasma, by binding to IGF-1 , forming a ternary complex with a labile subunit whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life decreasing the levels of free IGF-1 in plasma in individuals who need it. This composition comprises pectin with a minimum of 65% D-galacturonic acid and papain with a proteolytic activity of at least 6,000 U/mg, where papain and pectin are moistened by at least two C3-6 polyols, and adjusted to approximately pH = 6 obtained with the addition of at least one C2-6 alkanolamide, together with an emulsifier, preservatives, and pharmaceutically acceptable solvents.

Preferably, C3-6 polyol used in the oral composition of the invention is 1 ,2,3- propanetriol (glycerin), 1 ,2-propanediol (propylene glycol), 1 ,3-butanediol, -1 ,4- butanediol, 1 ,3-butenodiol, 2,3-butenodiol, 2, 2-dimethyl-1 ,3-propanediol (neopentyl glycol), erythritol, sorbitol (70%), mannitol, or a combination of at least two of them. More preferably, the C3-6 polyol used is a combination of 1 ,2-propanediol (propylene glycol) and sorbitol (70%).

Propylene glycol, or propane-1 ,2-diol, is an organic compound, an alcohol or more precisely a diol, colorless, tasteless and odorless. Propylene glycol is a clear oily liquid, hygroscopic and miscible with water, acetone and chloroform. It is obtained by hydration of propylene oxide.

Sorbitol (70%) is a polyol, a hexahydrous alcohol of the same family as glycerin, very soluble in water and ethanol. Sorbitol is a colorless, odorless, sweet-tasting liquid. It is a humectant for cosmetic and pharmaceutical use and a food sweetener. It is resistant to acid, alkaline and bacterial attack, heat stable, non-toxic, and non volatile. It has the ability to sequester metal ions and is non-flammable.

On the other hand, C2-6 alkanolamine used in the composition according to the present invention to neutralize the acid pH may be monoethanolamine, diethanolamine, or triethanolamine. Preferably, the C2-6 alkanolamine used is triethanolamine.

Triethanolamine is an organic chemical compound formed mainly by a tertiary amine and three hydroxyl groups, of general chemical formula C6H15NO3. Like other amines, triethanolamine acts as a weak chemical base due to the electron pair available on the nitrogen atom.

Triethanolamine occurs as a viscous liquid, although when impure it may occurs as a temperature-dependent solid, limpid, pale yellow or colorless, little hygroscopic and volatile, totally soluble in water and miscible with most oxygenated organic solvents. Triethanolamine has a mild ammoniacal odor.

This chemical is used to adjust the pH in cosmetic preparations, hygiene preparations, and cleaning products. Cosmetic and hygiene products in which it is used for this purpose include skin lotions, eye gels, moisturizers, shampoos, shaving foams, and so on.

In a preferred embodiment of the composition of the present invention is also used a non-ionic emulsifier which is selected from the group consisting on: polyoxyethylene (8) stearate (E-430); polyoxyethylene (40) stearate (E-431 ); polyoxyethylene (20) monolaurate (20 OE or ethoxylated with 20 oxyethylene groups) sorbitan (also known as polysorbate 20, Tween20 or E-432); polyoxyethylene (20) sorbitan monooleate (polysorbate 80, Tween 80 or E-433); polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40, Tween 40 or E-434); polyoxyethylene (20) sorbitan monostearate (polysorbate 60, Tween 60 or E-435); polyoxyethylene (20) sorbitan tristearate (polysorbate 65, Tween 65 or E-436); and mixtures thereof.

In particular, according to a preferred embodiment of the composition of the invention, as a non-ionic emulsifier, polyoxyethylene (20) sorbitane monolaurate (Tween 20) is used.

Tween 20 is a food additive with the action of a non-ionic detergent of lipophilic character that emulsifies and dissolves fats. Tween 20 is a substance approved by the European Union for use in foods and is named as Emulsifier 433 (E-433).

Finally, the preservative used in the oral composition is selected from the group consisting on methylparaben, ethylparaben, propylparaben, and mixtures thereof. Preferably, a mixture of methylparaben and propylparaben is used in a preferred embodiment of the composition of the present invention.

Preferably, the pectin is apple bagasse pectin or citrus pectin. More preferably, the pectin used is citrus pectin.

A preferred embodiment of the oral composition in soft capsule of the invention comprises citrus pectin between approximately 20.00% and approximately 35.00% w/w, preferably in the order of 25.00% w/w; papain (of at least 6,000 U/mg) between approximately 0.10% w/w and approximately 1.00% w/w, preferably in the order of 0.30% w/w; propylene glycol between approximately 30.00% w/w and approximately 55.00% w/w, preferably in the order of 40.00% w/w; triethanolamine (99%) between approximately 2.00% w/w and approximately 4.00% w/w, preferably in the order of 3.00% w/w; polyoxyethylene sorbitan monolaurate with 20 OE (Tween 20) between approximately 1.00% w/w and approximately 3.00% w/w, preferably in the order of 2.00% w/w; sorbitol (70%) between approximately 10.00% w/w and approximately 20.00% w/w, preferably in the order of 15% w/w; methylparaben between approximately 0.05% w/w and approximately 0.30% w/w, preferably in the order of 0.10% w/w; propylparaben between approximately 0.02% w/w and approximately 0.20% w/w, preferably in the order of 0.05% w/w; and sterile water q.s. to 100% w/w. The secondary ingredients used in the composition are also used in the food industry, thus providing extensive toxicological safety.

Another object of the present invention is a method to prepare the oral composition in soft capsules of citrus pectin and papain to increase plasma levels of transport protein IGFBP-3 by binding to IGF-1 , forming a ternary complex with a labile subunit whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life decreasing plasma free IGF-1 levels in individuals who need it.

As described above, the method comprises:

(b) lower stirring rate to approximately 300 rpm and add a non-ionic emulsifier, pectin, and then a C2-6 alkanolamine until the acidity of the pectin is neutralized and a dispersion at approximately pH = 6 is formed; and

c) add another C3-6 polyol and finally complete with sterile water up to total weight forming a stable gel. In a preferred embodiment, the method described comprises:

(b) lower stirring rate to 300 rpm and add polyoxyethylene sorbitan monolaurate with 20 EC, then citrus pectin and then triethanolamine (99%) until the acidity of citrus pectin is neutralized and a dispersion at approximately pH = 6 is formed; and c) add sorbitol (70%) and complete with sterile water up to 100% w/w forming a stable gel.

In a preferred embodiment, stirring during step a) is performed at approximately 500 rpm and stirring during step b) and c) is performed at approximately 300 rpm to approximately 350 rpm.

Once the oral composition is obtained, it is analyzed to verify that it is in conditions to be fractionated. For this purpose, the method involves step (d) of packaging the gel obtained into soft gelatin capsules of a pharmaceutically acceptable quality.

In this way, the gel is packaged into soft gelatin capsules, e.g., with a capacity of approximately 1 ,000 mg. Secondary packaging is carried out in blisters of, e.g., fifteen (15) capsules each, tertiary packaging being carried out in cardboard boxes containing, e.g., four blisters and the corresponding package leaflet. Box ends are glued together in order to make them tamper-resistant.

The quantities of capsules per blister and blisters per box are variable and can be adjusted as required.

In a preferred embodiment the oral composition in syrup of the invention comprises citrus pectin between approximately 2.00% w/w and approximately 10.00% w/w, preferably in the order of 5.00% w/w; papain (of at least 6,000 U/mg) between approximately 0.05% w/w and approximately 0.50% w/w, preferably in the order of 0.06% w/w; propylene glycol between approximately 5.00% w/w and approximately 15.00% w/w, preferably in the order of 10.00% w/w; triethanolamine (99%) between approximately 0.20% w/w and approximately 1.00% w/w, preferably in the order of 0.80% w/w; polyoxyethylene sorbitan monolaurate with 20 OE (Tween 20) between approximately 0.20% w/w and approximately 1.00% w/w, preferably in the order of 0.40% w/w; sorbitol (70%) between approximately 15.00% w/w and approximately 30.00% w/w, preferably in the order of 20% w/w; vanilla essence between approximately 0.20% w/w and approximately 0.50% w/w, preferably in the order of 0.35% w/w; methylparaben between approximately 0,05% w/w and approximately 0,30% w/w, preferably in the order of 0,10% w/w; propylparaben between approximately 0,02% w/w and approximately 0,20% w/w, preferably in the order of 0,05% w/w, and sterile water q.s. to 100% w/w.

The secondary components used are also used in the food industry and therefore provide extensive toxicological safety.

It is another object of the present invention, a method to prepare the oral composition in syrup of pectin and papain to increase the levels of the transport protein IGFBP-3 in plasma by binding IGF-1 , forming a ternary complex with a labile subunit whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life reducing the levels of free IGF-1 in plasma in individuals who need it.

As described above, the method comprises:

a) add under stirring at approximately 400 rpm a C3-6 polyol and disperse papain of at least 6,000 U/mg, methylparaben, and propylparaben;

(b) lower stirring rate to approximately 300 rpm and add at least one non-ionic emulsifier, pectin, and then at least one C2-6 alkanolamine until the acidity of the pectin is neutralized and a dispersion at approximately pH = 6 is formed; and c) add then at least another C3-6 polyol, essence and complete with sterile water q.s. to 100% by weight forming a stable syrup.

Preferably, method described comprises a) add under stirring at approximately 400 rpm propylene glycol and disperse papain of at least 6,000 U/mg, methylparaben, and propylparaben;

(b) lower stirring rate to approximately 300 rpm and add polyoxyethylene sorbitan monolaurate with 20 OE, citrus pectin and then triethanolamine (99%) until the acidity of citrus pectin is neutralized and a dispersion at approximately pH = 6 is formed; and

c) add then sorbitol (70%), vanilla essence and complete with sterile water q.s. to 100% by weight forming a stable syrup.

Preferably, stirring during step a) is performed at approximately 400 rpm, and stirring during step b) and c) is performed between approximately 250 rpm and approximately 300 rpm.

Once the composition is obtained, it is analyzed to verify that it is in conditions to be fractionated. For this purpose, the method includes the step (d) of packing the syrup obtained into dark bottles, preferably dark glass or plastic bottles, with tamper-proof caps of a pharmaceutically acceptable material.

In a preferred embodiment, the syrup is packaged into dark plastic jars, e.g. of approximately 120 ml_ and approximately 250 ml_ capacity. The secondary packaging is carried out into cardboard boxes containing the bottle with the syrup and the corresponding leaflet. Box ends are glued together in order to make them tamper-resistant.

It is still another object of the present invention a method to diminish the levels of free IGF-1 in plasma of individuals who need it using the oral composition according to the present invention, comprising administering to these individuals a dosage comprising at least 250 mg of pectin and at least about 3 mg of papain every at least 12 hours during at least 28 days.

This method achieves the decrease of free IGF-1 levels in plasma is within the range of approximately 50% to approximately 70%. Preferably, the pectin is apple bagasse pectin or citrus pectin. More preferably, the pectin used is citrus pectin.

Also, the composition of the invention achieves increased levels of plasma transport protein IGFBP-3 which, when binds to IGF-1 , forms a ternary complex with a labile subunit whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life thus reducing free IGF-1 levels.

Thus, the increase in plasma transport protein IGFBP-3 levels is within the range of approximately 30% to approximately 60% achieving the method’s goal of reducing free IGF-1 levels.

As applied in the method, the at least about 250 mg of pectin, preferably citrus pectin, and the at least about 3 mg of papain are in dosage forms of soft capsules or each approximately 5 ml_ of syrup.

A method for decreasing the plasma free IGF-1 levels in individuals who need it to treat malignant neoplasms, diabetes, neuropsychiatric disorders, and cardiovascular diseases using the oral composition as described above, administering to such individuals a dosage comprising at least about 250 mg of pectin and at least about 3 mg of papain every 12 hours for at least 28 days.

It is also still another object of the present invention, the use of pectin and papain together to prepare an oral composition as described above, useful to reduce the levels of free IGF-1 in plasma of individuals who need it, by administering to such individuals a dosage comprising at least 250 mg of pectin and at least 3 mg of papain every 12 hours for at least 28 days.

According to such use, the decrease in plasma free IGF-1 levels is within the range of approximately 50% to approximately 70%.

Preferably, the pectin used is apple bagasse pectin or citrus pectin. More preferably, the pectin used is citrus pectin.

In addition, by means of the described use it is possible to increase the levels of the transport protein IGFBP-3 in plasma that, when binds to IGF-1 , forms a ternary complex with a labile subunit whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life reducing the levels of free IGF- 1 .

Also, through such use, plasma levels of transport protein IGFBP-3 are increased within the range of approximately 30% to approximately 60%.

Preferably, the at least about 250 mg of pectin and the at least about 3 mg of papain are in dosage forms of soft capsules or each approximately 5 ml_ of syrup.

EXAMPLES

Example 1 : Manufacture of the oral composition of the invention in soft capsules.

One hundred kg, equivalent to 100,000 capsules of 1 ,000 mg each, of the oral composition were manufactured in a reactor with stirring to fill soft capsules comprising 250 mg of citrus pectin and 3 mg of papain.

Forty kg of propylene glycol were loaded into a 100 L 316 stainless steel reactor fitted with a W-shaped flat paddle for gel stirring, and 0.300 kg of papain of at least 6,000 U/mg, 0.100 kg of methylparaben and 0.050 kg of propylparaben were added with stirring at 500 rpm. The stirring was maintained for 10 minutes until a stable emulsion was achieved and then the stirring was lowered to 300 rpm and 2 kg of polyoxyethylene sorbitan with 20 OE, 25 kg of citrus pectin, and 3 kg of triethanolamine (99%) were added up to a pH = 6, forming a stable dispersion.

Fifteen kg of sorbitol (70%) and 19.55 kg of sterile water were added while stirring. The stirring was maintained for 20 minutes forming a stable gel.

The stirring was stopped and a sample was taken for quality control tests of pH, stability and viscosity. The gel obtained was then packaged into soft gelatin capsules of 1 ,000 mg each.

Secondary packaging was carried out in blisters of fifteen (15) capsules each, tertiary packaging was carried out in cardboard boxes containing four blisters and the corresponding leaflet.

Example 2: Manufacture of the oral composition of the invention in syrup.

One thousand L of the oral composition in syrup, each 5 ml_ containing 250 mg of citrus pectin and 3 mg of papain, were manufactured in a reactor with stirring.

One hundred kg of propylene glycol were loaded into a 1 ,200 L 316 stainless steel reactor fitted with a disc turbine and four paddles for syrup stirring and 0.600 kg of papain of at least 6,000 U/mg, 1 kg of methylparaben, and 0.500 kg of propylparaben were added with stirring at 400 rpm, the stirring was maintained for 8 minutes until a stable emulsion was achieved and then the stirring was lowered to 300 rpm and 4 kg of polyoxyethylene sorbitan with 20 OE, 50 kg of citrus pectin, and 8 kg of triethanolamine (99%) were added up to pH = 6, forming a stable dispersion. Two hundred kg of sorbitol (70%) and 3.5 kg of vanilla essence were added with stirring and sterile water was added up to 1 ,000 L of total volume, maintaining stirring for 20 minutes until a stable syrup was formed.

The stirring was stopped and a sample was taken for quality control (pH, stability and viscosity). The syrup obtained was then packaged into 250 ml_ dark bottles with tamper-proof caps and labeled.

Tertiary packaging was carried out in cardboard boxes containing a bottle and the respective leaflet.

Example 3: Clinical trial in individuals who need it to determine the effective ratio between citrus pectin and papain of the present invention.

Objective: To determine the effective ratio between citrus pectin and papain for an oral composition.

Materials and methods: A randomized clinical trial was conducted. The patients were randomly assigned to a group, where they received a soft capsule of the specific oral composition twice a day. The concentration of insulin-like growth factor 1 (IGF-1 ) was determined by a radiometric method (IRMA).

Results: 90 patients participated in this study, which were randomly divided into 9 groups of 10 patients each according to Table 1 .

The patients received a treatment consisting of 2 soft capsules per day, 1 every 12 hours, for 28 days, according to the formulation corresponding to each group. The results of clinical laboratory analyses of patients at the start of treatment and then every 7 days for 28 days of treatment are shown in Table 2. Patients had a mean age of 42.0 years old (SD = 18.98), where the minimum was 25 and the maximum was 65 years old.

Table 1 : Study groups according to citrus pectin :papain ratio.

Table 2: Plasma free IGF-1 levels.

Conclusions: The lowest values of free IGF-1 were obtained with the ratios G100:5, G250:3 and G500:3, with the ratio G250:3 having the highest rate of relative reduction of 67.4%.

No side effects were observed in any patient.

APPLICATION EXAMPLES

Application example 1 : Clinical trial to know the effect of the oral composition in soft capsules containing citrus pectin and papain on the levels of IGFBP-3 and IGF-1 in individuals who need it.

Objective: To know the effect of the oral composition in soft capsules containing citrus pectin 250 mg and papain 3 mg on the levels of IGFBP-3 and IGF-1 in individuals who need it. To know the side effects on blood glucose, basal insulin, and creatinine.

Materials and methods: A blinded, randomized clinical trial was conducted. Patients were randomly assigned to receive either a soft capsule of oral composition (capsule with citrus pectin 250 mg, papain 3 mg, and excipients) twice daily or a placebo (capsule only with excipients) twice daily. Plasma concentration of insulin-like transporter protein 3 (IGFBP-3) was determined by a chemiluminescent method, insulin-like growth factor 1 (IGF-1 ) by radiometric method (IRMA), basal insulinemia by an electrochemiluminescent method, glucose by a Glucose Oxidase and Peroxidase (GOD-PAP) enzymatic method, and blood creatinine by Jaffe method without deproteinization. These determinations were performed at the beginning of treatment, at 14 days, and at the end of treatment, i.e. after 28 days.

Results: 103 patients participated in this study, who were assigned to treatment according to a table of random numbers in which the following distribution was obtained: 52 (50.49%) received treatment with 1 soft capsule (with citrus pectin 250 mg, papain 3 mg, and excipients) every 12 hours for 28 days and 51 (49.51 %) received placebo, 1 capsule (only with excipients) every 12 hours for 28 days. The results of clinical laboratory analyses of patients at the beginning of treatment are shown in Table 3. Patients had a mean age of 52.0 years old (SD = 12.54), where the minimum was 27 and the maximum 75 years old.

Table 3: Clinical laboratory analyses at the beginning of treatment.

After 14 days of treatment, an increase of 29.54% in plasma IGFBP-3 levels and a decrease of 37.42% in IGF-1 levels for the oral soft capsule composition were observed (Table 4), while blood glucose, basal insulin, and creatinine values remain normal. For placebo, plasma IGFBP-3 levels increased by 2.64% and IGF-1 levels decreased by 3.07% were observed, while blood glucose, basal insulin, and creatinine values remained normal.

Table 4: Clinical laboratory analysis after 14 days of treatment.

After 28 days of treatment, an increase of 45.81 % in plasma IGFBP-3 levels and a decrease of 54.97% in IGF-1 levels for the oral soft capsule composition were observed (Table 5), while blood glucose, basal insulin, and creatinine values remain normal. For placebo, plasma IGFBP-3 levels increased by 1.81 % and IGF-1 levels decreased by 4.60% were observed, while blood glucose, basal insulin, and creatinine values remained normal.

Table 5: Clinical laboratory analysis after 28 days of treatment.

Conclusions: The oral composition in soft capsules of citrus pectin 250 mg and papain 3 mg increases the plasma levels of IGFBP-3 and decreases the levels of free IGF-1 in individuals who need it effectively compared to placebo. Blood glucose, basal insulinemia, and creatinine values remain normal during treatment.

Application example 2: Clinical trial to know the effect of the oral composition in syrup containing citrus pectin and papain on the levels of IGFBP-3 and IGF- 1 in individuals who need it.

Objective: To know the effect of the oral composition in syrup (each 5 ml_ containing citrus pectin 250 mg and papain 3 mg, plus excipients) on the levels of IGFBP-3 and IGF-1 in individuals who need it. To know the side effects on blood glucose, basal insulin, and creatinine.

Materials and methods: A blinded, randomized clinical trial was conducted. Patients were randomly assigned to receive 5 ml_ of the oral composition in syrup (comprising citrus pectin 250 mg, papain (at least 6,000 U/mg) 3 mg, and excipients) twice daily or a placebo (a syrup only with excipients) twice daily. Plasma concentration of insulin-like transporter protein 3 (IGFBP-3) was determined by a chemiluminescent method, insulin-like growth factor 1 (IGF-1 ) by a radiometric method (IRMA), basal insulinemia by an electrochemiluminescent method, blood glucose by GOD-PAP method, and creatinine by Jaffe method without deproteinization. These determinations were performed at the beginning of treatment, at 14 days, and at the end of treatment after 28 days.

Results: This trial included 102 patients who were assigned to treatment according to a table of random numbers in which the following distribution was obtained: 50 (49.02%) received treatment of 5 ml_ of syrup (containing citrus pectin 250 mg, papain 3 mg, and excipients) every 12 hours for 28 days and 52 (50.98%) received placebo of 5 ml_ of syrup (containing only excipients) every 12 hours for 28 days. The results of clinical laboratory analyses of patients at the beginning of treatment are shown in Table 6. Patients had a mean age of 47.0 years old (SD = 10.89), where the minimum was 29 and the maximum was 68 years old.

Table 6: Clinical laboratory analyses at the beginning of treatment

After 14 days of treatment, an increase of 33.32% in plasma IGFBP-3 levels and a decrease of 41 .32% in IGF-1 levels for the oral syrup composition were observed (Table 7), while blood glucose, basal insulin, and creatinine values remain normal. For placebo, plasma IGFBP-3 levels increased by 0.58% and IGF-1 levels decreased by 2.77%, while blood glucose, basal insulin, and creatinine values remained normal.

Table 7: Clinical laboratory analysis after 14 days of treatment.

After 28 days of treatment, an increase of 34.98% in plasma IGFBP-3 levels and a decrease of 56.59% in IGF-1 levels for the oral syrup composition were observed (Table 8), while blood glucose, basal insulin, and creatinine values remain normal. For placebo, plasma IGFBP-3 levels increased by 1 .74% and IGF-1 levels decreased by 1 .05%, while blood glucose, basal insulin, and creatinine values remained normal.

Table 8: Clinical laboratory analysis after 28 days of treatment.

Conclusions: The oral composition in syrup in doses of 5 ml_ containing citrus pectin 250 mg, papain 3 mg, and excipients achieves increased levels of IGFBP-3 and decreased plasma levels of IGF-1 in individuals who need it effectively compared to placebo. Blood glucose, basal insulinemia, and creatinine values remain normal during treatment.

Application example 3: Clinical trial to know the effect of the oral composition in syrup containing apple bagasse pectin and papain on the levels of IGFBP-3 and IGF-1 in individuals who need it.

Objective: To know the effect of the oral composition in syrup (each 5 ml_ containing apple bagasse pectin 250 mg and papain 3 mg, plus excipients) on the levels of IGFBP-3 and IGF-1 in healthy adults. To know the side effects on blood glucose, basal insulinemia, and creatinine.

Materials and methods: A blinded, randomized clinical trial was conducted. Patients were randomly assigned to receive 5 ml_ of the oral composition in syrup (comprising 250 mg of apple bagasse pectin, 3 mg of papain (at least 6,000 U/mg), and excipients) twice daily or a placebo (a syrup with excipients) twice daily. Plasma concentration of insulin-like transporter protein 3 (IGFBP-3) was determined by a chemiluminescent method, insulin-like growth factor 1 (IGF-1 ) by a radiometric method (IRMA), basal insulinemia by an electrochemiluminescent method, blood glucose by GOD-PAP method, and creatinine by Jaffe method without deproteinization. These determinations were performed at the beginning of treatment, at 14 days, and at the end of treatment, after 28 days.

Results: This trial included 102 patients who were assigned to treatment according to a table of random numbers in which the following distribution was obtained. 51 (50.00%) received treatment of 5 ml_ of syrup (containing 250 mg of apple bagasse pectin, 3 mg of papain, and excipients) every 12 hours for 28 days and 51 (50.00%) received placebo of 5 ml_ of syrup (containing only excipients) every 12 hours for 28 days. The results of clinical laboratory analyses of patients at the beginning of treatment are shown in Table 9. Patients had a mean age of 45.0 years old (SD = 1 1.91 ), where the minimum was 25 and the maximum was 74 years old.

Table 9: Clinical laboratory analyses at the beginning of treatment

After 14 days of treatment, an increase in plasma levels of IGFBP-3 of 29.84% and a decrease in IGF-1 levels of 40.11 % for the oral syrup composition were observed (Table 10), while blood glucose, basal insulinemia, and creatinine values remain normal. For placebo, plasma IGFBP-3 levels increased by 1.51 % and IGF-1 levels decreased by 4.61 %, while blood glucose, basal insulinemia, and creatinine values remained normal.

Table 10: Clinical laboratory analysis after 14 days of treatment.

After 28 days of treatment, an increase of 33.87% in plasma IGFBP-3 levels and a decrease of 53.38% in IGF-1 levels for the oral syrup composition were observed (Table 1 1 , while blood glucose, basal insulinemia, and creatinine values remain normal. For placebo, plasma IGFBP-3 levels increased by 2.1 1 % and IGF-1 levels decreased by 5.36%, while blood glucose, basal insulinemia, and creatinine values remained normal.

Table 1 1 : Clinical laboratory analysis after 28 days of treatment.

Conclusions: The oral composition in syrup in doses of 5 ml_ containing apple bagasse pectin 250 mg, papain 3 mg, and excipients achieves increased levels of IGFBP-3 and decreased plasma levels of IGF-1 in adults who need it effectively compared to placebo. Blood glucose, basal insulinemia, and creatinine values remain normal during treatment.

Application example 4: Clinical trial in adults with diabetes mellitus type 2 to know the effect of the oral composition in syrup containing citrus pectin and papain on the levels of IGFBP-3, IGF-1 , basal insulinemia, and blood glucose.

Objective: To know the effect of the oral composition in syrup (each 10 ml_ containing citrus pectin 500 mg and papain 6 mg, plus excipients) on the levels of IGFBP-3, IGF-1 , basal insulinemia, and blood glucose in adults with type 2 diabetes mellitus. To know the side effects on creatinine.

Materials and methods: A blinded, randomized clinical trial was conducted. Patients were randomly assigned to receive 10 ml_ of the oral composition in syrup (comprising 500 mg citrus pectin, papain (at least 6,000 U/mg) 6 mg, and excipients) twice daily or a placebo (a syrup with only excipients) twice daily. Plasma concentration of insulin-like transporter protein 3 (IGFSP-3) was determined by a chemiluminescent method, insulin-like growth factor 1 (IGF-1 ) by a radiometric method (IRLA), basal insulinemia by an electrochemiluminescent method, blood glucose by GOD-PAP method, and creatinine by Jaffe method without deproteinization. These determinations were performed at the beginning of treatment, at 14 days, and at the end of treatment, after 28 days.

Results: This trial included 40 patients with type 2 diabetes mellitus on metformin 850 mg twice daily (1 ,700 mg daily), who had a poor response to treatment, elevated blood glucose levels, and were considered candidates for insulin treatment. Patients were assigned to treatment according to a table of random numbers in which the following distribution was obtained: 21 (52.50%) received treatment of 10 ml_ of syrup (containing citrus pectin 500 mg, papain 6 mg, and excipients) every 12 hours for 28 days and 19 (49.50%) received placebo of 10 ml_ of syrup (containing excipients) every 12 hours for 28 days. Both groups maintained the current dose of metformin. The results of clinical laboratory analyses of patients at the beginning of treatment are shown in Table 12. Patients had a mean age of 55.4 years old (SD = 15.40), where the minimum was 35 and the maximum was 72 years old.

Table 12: Clinical laboratory analyses at the beginning of treatment

After 14 days of treatment, an increase of 39.65% in plasma IGFBP-3 levels, a 17.07% decrease in IGF-1 levels, a 32.43% decrease in blood glucose, and a 22.72% decrease in basal insulinemia for the oral syrup composition were observed (Table 13), while creatinine values remain normal. For placebo, plasma IGFBP-3 levels increased by 0.91 %, IGF-1 levels decreased by 2.63%, blood glucose decreased by 2.86%, and basal insulin decreased by 1 .75%, while creatinine values remained normal.

Table 13: Clinical laboratory analysis after 14 days of treatment.

After 28 days of treatment, Table 14 shows an increase of 45.48% in plasma IGFBP- 3 levels, a 34.63% decrease in IGF-1 levels, a 63.78% decrease in blood glucose, and a 46.55% decrease in basal insulinemia for the oral syrup composition, while creatinine values remain normal. For placebo, plasma IGFBP-3 levels increased by 3.63%, IGF-1 levels decreased by 4.74%, blood glucose decreased by 3.43%, and basal insulin decreased by 2.63%, while creatinine values remained normal.

Table 14: Clinical laboratory analysis after 28 days of treatment.

Conclusions: The oral composition in syrup in doses of 10 ml_ containing citrus pectin 500 mg, papain 6 mg, and excipients increases levels of IGFBP-3, decreases plasma levels of IGF-1 , decreases blood glucose levels, and basal insulinemia levels in adults with type 2 diabetes mellitus effectively compared to placebo. Creatinine values remain normal during treatment.

Application example 5: Clinical trial in adults with colorectal malignancy to know the effect of the oral composition in syrup containing citrus pectin and papain on IGFBP-3, IGF-1 , and CEA levels.

Objective: To know the effect of the oral composition in syrup (where each 10 ml_ contains citrus pectin 500 mg and papain 6 mg, plus excipients) on the levels of IGFBP-3, IGF-1 , and CEA in adults with colorectal malignancy. To know the side effects on blood glucose, basal insulinemia, and creatinine.

Materials and methods: A blinded, randomized clinical trial was conducted. Patients were randomly assigned to receive 10 ml_ of the oral composition in syrup (comprising 500 mg citrus pectin, papain (at least 6,000 U/mg) 6 mg, and excipients) twice daily or placebo (one syrup with only excipients) twice daily. Plasma concentration of insulin-like transporter protein 3 (IGFBP-3) was determined by a chemiluminescent method, insulin-like growth factor 1 (IGF-1 ) by a radiometric method (IRMA), carcinoembryonic antigen (CEA) by a chemiluminescence method (ICMA), basal insulinemia by an electrochemiluminescent method, blood glucose by GOD-PAP method, and creatinine by Jaffe method without deproteinization. These determinations were performed at the beginning of treatment, at 14 days, and at the end of treatment, after 28 days.

Results: This trial included 20 patients with colorectal cancer, who were subjected to surgery and without chemotherapy, patients were assigned to treatment according to a table of random numbers in which the following distribution was obtained: 1 1 (55.00%) received treatment of 10 mL of syrup (containing citrus pectin 500 mg, papain 6 mg, and excipients) every 12 hours for 28 days and 9 (45.00%) received placebo of 10 mL of syrup (containing only excipients) every 12 hours for 28 days. The results of clinical laboratory analyses of patients at the beginning of treatment are shown in Table 15. Patients had an average age of 80.4 years old (SD = 5.20), where the minimum was 75 years and the maximum was 87 years old.

Table 15: Clinical laboratory analyses at the beginning of treatment

After 14 days of treatment; an increase of 20.87% in plasma IGFBP-3 levels, a decrease of 19.61 % in IGF-1 levels, and a decrease of 26.37% in CEA levels for the oral syrup composition were observed (Table 16), blood glucose, basal insulinemia, and creatinine remain normal. For placebo, plasma IGFBP-3 levels increased by 0.63%, IGF-1 levels decreased by 1.70%, and CEA levels increased by 2.47%. Blood glucose, basal insulinemia, and creatinine remain normal.

Table 16: Clinical laboratory analysis after 14 days of treatment.

After 28 days of treatment, a 32.66% increase in plasma IGFBP-3 levels, a 47.45% decrease in IGF-1 levels, and a 68.13% decrease in CEA levels for the oral syrup composition were observed, blood glucose, basal insulinemia, and creatinine remain normal. For placebo, an increase in plasma IGFBP-3 levels of 1.90%, a decrease in IGF-1 levels of 2.55.%, and an increase in CEA levels of 3.70% were observed. Blood glucose, basal insulinemia, and creatinine remain normal.

Table 17: Clinical laboratory analysis after 28 days of treatment.

Conclusions: The oral composition in syrup in doses of 10 ml_ containing citrus pectin 500 mg, papain 6 mg, and excipients achieves increased levels of IGFBP-3, decreased plasma levels of IGF-1 , and decreased plasma levels of CEA (carcinoembryonic antigen) in adults with colorectal malignancy effectively compared to placebo. Blood glucose, basal insulinemia, and creatinine values remain normal during treatment.

COMPARATIVE EXAMPLES

Comparative example 1 : Clinical trial of plasma IGF-1 levels comparing soft capsules of modified citrus pectin with soft capsules of citrus pectin and papain in individuals who need it.

Objective: In this comparative study, the effects of modified citrus pectin on IGF-1 levels and the effects of citrus pectin plus papain on IGF-1 levels in individuals who need it were investigated.

Materials and Methods: A blinded, randomized clinical trial was conducted. Patients were randomly assigned to receive one soft capsule (modified citrus pectin 250 mg plus excipients) twice daily or one soft capsule of oral composition (comprising citrus pectin 250 mg, papain (at least 6,000 U/mg) 3 mg, and excipients) twice daily. Plasma concentration of insulin-like transporter protein 3 (IGFBP-3) was determined by a chemiluminescent method, and insulin-like growth factor 1 (IGF-1 ) by a radiometric method (IRMA).

Results: 21 patients participated in this study, who were assigned to the treatment according to a table of random numbers in which the following distribution was obtained: 1 1 (52.38%) received treatment with a soft capsule (of modified citrus pectin 250 mg plus excipients) one every 12 hours during 28 days and 10 (47.62%) received a soft capsule of oral composition (comprising citrus pectin 250 mg, papain 3 mg, and excipients) every 12 hours during 28 days.

After treatment, the first group obtained an average decrease in IGF-1 of 30.8% as shown in Table 18 and the second group obtained an average decrease in IGF-1 of 62.6% as shown in Table 19. Patients 6 and 9 of the first group had mild side effects, diarrhea and intestinal cramps at 2 days and 3 days, respectively, after starting treatment, which was discontinued. The second group had no side effects.

Table 18: Plasma IGF-1 levels in group 1 .

Table 19: Plasma IGF-1 levels in group 2.

Conclusions: It can be observed that the decrease in IGF-1 of the second group is quantitatively remarkable over the first group, making evident the increase of clinical efficacy and the lack of side effects produced by the combination of citrus pectin with papain over the modified citrus pectin alone.

Comparative example 2: Clinical trial of plasma IGF-1 levels comparing modified citrus pectin syrup with citrus pectin syrup and papain in individuals who need it.

Objective: This comparative study investigated the effects of modified citrus pectin in syrup on IGF-1 levels and the effects of citrus pectin plus papain in syrup on IGF-1 levels in individuals who need it.

Materials and Methods: A blinded, randomized clinical trial was conducted. Patients were randomly assigned to receive 5 ml_ of syrup (modified citrus pectin 250 mg plus excipients) twice a day or 5 ml_ of oral composition syrup (comprising citrus pectin 250 mg, papain (at least 6,000 U/mg) 3 mg, and excipients) twice a day. Plasma concentration of insulin-like transporter protein 3 (IGFBP-3) was determined by a chemiluminescent method, and insulin-like growth factor 1 (IGF-1 ) by a radiometric method (IRMA).

Results: 20 patients participated in this study, who were assigned to the treatment according to a table of random numbers in which the following distribution was obtained: 10 (50.00%) received treatment with syrup (modified citrus pectin 250 mg plus excipients) 5 ml_ every 12 hours for 28 days and 10 (50.00%) received syrup of the oral composition (comprising citrus pectin 250 mg, papain 3 mg, and excipients) 5 ml_ every 12 hours for 28 days.

After treatment, the first group obtained an average decrease in IGF-1 of 29.4% as shown in Table 20 and the second group obtained an average decrease in IGF-1 of 58.2% as shown in Table 21. Patient 7 of the first group presented mild side effects of diarrhea after 8 days of treatment and was therefore discontinued. The second group had no side effects.

Table 20: Plasma IGF-1 levels in group 1.

Table 21 : Plasma IGF-1 levels in group 2.

Claims

1. An oral composition based on pectin and papain to reduce the levels of free IGF-1 in plasma of individuals who need it, this composition is CHARACTERIZED by comprising pectin of at least 65% of D-galacturonic acid and papain with a proteolytic activity of at least 6,000 U/mg, where pectin and papain have an effective weight ratio of approximately 250:3, respectively, and are moistened by means of at least two C3-6 polyols, being the pH of the composition in the order of 6 obtained with the addition of at least one C2-6 alkanolamide, and also comprising emulsifiers, preservatives, and pharmaceutically acceptable solvents.

2. The composition according to the claim, CHARACTERIZED by the C3-6 polyol is 1 ,2,3-propanetriol (glycerin), 1 ,2-propanediol (propylene glycol), 1 ,3-butanediol, 1 ,4- butanediol, 1 ,3-butenodiol, 2,3-butenodiol, 2, 2-dimethyl-1 ,3-propanediol (neopentyl glycol), erythritol, sorbitol (70%), mannitol, or a combination of either of these.

3. The composition according to claim 2, CHARACTERIZED by the C3-6 polyol is a combination of 1 ,2-propanediol (propylene glycol) and sorbitol (70%).

4. The composition according to claim 1 , CHARACTERIZED by the pectin is apple bagasse pectin or citrus pectin.

5. The composition according to claim 4, CHARACTERIZED by the pectin used is citrus pectin.

6. The composition according to claim 1 , CHARACTERIZED by the C2-6 alkanolamine is selected from the group consisting of monoethanolamine, diethanolamine, triethanolamine, and mixtures thereof.

7. The composition according to claim 6, CHARACTERIZED by the C2-6 alkanolamine is triethanolamine.

8. The composition according to claim 1 , CHARACTERIZED by the non-ionic emulsifier is selected from the group consisting of polyoxyethylene (8) stearate (E- 430); polyoxyethylene (40) stearate (E-431 ); polyoxyethylene (20) (20 OE or ethoxylated with 20 oxyethylene groups) sorbitan monolaurate (also known as polysorbate 20, Tween 20 or E-432); polyoxyethylene (20) sorbitan monostearate (polysorbate 80, Tween 80 or E-433); polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40, Tween 40 or E-434); polyoxyethylene (20) sorbitan monostearate (polysorbate 60, Tween 60 or E-435); polyoxyethylene (20) sorbitan tristearate (polysorbate 65, Tween 65 or E-436); and mixtures thereof.

9. The composition according to claim 8, CHARACTERIZED by the non-ionic emulsifier is polyoxyethylene (20) sorbitan monolaurate (Tween 20).

10. The composition according to claim 1 , CHARACTERIZED by the preservative is selected from the group consisting of methylparaben, ethylparaben, propylparaben, and mixtures thereof.

1 1. The composition according to claim 10, CHARACTERIZED by the preservative is a mixture of methylparaben and propylparaben.

12. The composition according to any of the claims 1 to 1 1 CHARACTERIZED by it is in a soft capsule dosage form.

13. The composition according to any of the claims 1 to 1 1 , CHARACTERIZED by it is in a syrup dosage form.

14. The composition according to claim 12, CHARACTERIZED by comprising citrus pectin between approximately 20.00% w/w and approximately 35.00% w/w, papain (of at least 6,000 U/mg) between approximately 0.10% w/w and approximately 1.00% w/w, propylene glycol between approximately 30.00% w/w and approximately 55.00% w/w, triethanolamine (99%) between approximately 2.00% w/w and approximately 4.00% w/w, polyoxyethylene sorbitan monolaurate with 20 OE (Tween 20) between approximately 1.00% w/w and approximately 3.00% w/w, sorbitol (70%) between approximately 10.00% w/w and approximately 20.00% w/w, methylparaben between approximately 0.05% w/w and approximately 0.30% w/w, propylparaben between approximately 0.02% w/w and approximately 0.20% w/w, and sterile water q.s. to 100% w/w.

15. The composition according to claim 14, CHARACTERIZED by comprising citrus pectin in the order of 25.00% w/w, papain (of at least 6,000 U/mg) in the order of 0.30% w/w, propylene glycol in the order of 40.00% w/w, triethanolamine (99%) in the order of 3.00% w/w, polyoxyethylene sorbitan monolaurate with 20 EO (Tween 20) in the order of 2.00% w/w, sorbitol (70%) in the order of 15% w/w, methylparaben in the order of 0.10% w/w, propylparaben in the order of 0.05% w/w, and sterile water q.s. to 100% w/w.

16. The composition according to claim 13, CHARACTERIZED by comprising citrus pectin between approximately 2.00% w/w and approximately 10.00% w/w, papain (of at least 6,000 U/mg) between approximately 0.05% w/w and approximately 0.50% w/w, propylene glycol between approximately 5.00% w/w and approximately 15.00% w/w, triethanolamine (99%) between approximately 0.20% w/w and approximately 1.00% w/w, polyoxyethylene sorbitan monolaurate with 20 EO (Tween 20) between approximately 0.20% w/w and approximately 1.00% w/w, sorbitol (70%) between approximately 15.00% w/w and approximately 30.00% w/w, vanilla essence between approximately 0.20% w/w and approximately 0.50% w/w, methylparaben between approximately 0.05% w/w and approximately 0.30% w/w, propylparaben between approximately 0.02% w/w and approximately 0.20% w/w, and sterile water q.s. to 100% w/w.

17. The composition according to claim 16, CHARACTERIZED by comprising citrus pectin in the order of 5.00% w/w, papain (at least 6,000 U/mg) in the order of 0.06% w/w, propylene glycol in the order of 10.00% w/w, triethanolamine (99%) in the order of 0.80% w/w, polyoxyethylene sorbitan monolaurate with 20 OE (Tween 20) in the order of 0.40% w/w, sorbitol (70%) in the order of 20% w/w, vanilla essence in the order of 0.35% w/w, methylparaben in the order of 0.10% w/w, propylparaben in the order of 0.05 w/w, and sterile water q.s. to 100% w/w.

18. A method to prepare the oral composition in the dosage form of soft capsule from claim 12, such a method CHARACTERIZED by comprising:

b) lower stirring speed to approximately 300 rpm and add a non-ionic emulsifier, pectin, and then at least one C2-6 alkanolamine until the acidity of the pectin is neutralized and a dispersion at approximately pH = 6 is formed;

c) add at least one other C3-6 polyol and complete finally with sterile water to full weight forming a stable gel; and

(d) encapsulate in soft capsules the stable gel obtained in step (c) above.

19. The method according to claim 18, CHARACTERIZED by comprising:

b) lower stirring speed to about 300 rpm and add polyoxyethylene sorbitan monolaurate with 20 OE, then citrus pectin, and then triethanolamine (99%) until the acidity of citrus pectin is neutralized and a dispersion at about pH = 6 is formed;

(d) encapsulate in soft capsules the stable gel obtained in step (c) above.

20. A method for preparing the oral composition in the dosage form of syrup from claim 13, such a method CHARACTERIZED by comprising:

a) add under stirring at approximately 400 rpm at least one C3-6 polyol and disperse papain of at least 6,000 U/mg, and at least one preservative;

(b) lower stirring rate to approximately 300 rpm and add at least one non-ionic emulsifier and then at least one C2-6 alkanolamine until the acidity of the pectin is neutralized and a dispersion at approximately pH = 6 is formed;

c) add then at least another C3-6 polyol, essence and complete with sterile water up to 100% w/w forming a stable syrup: and

d) fractionate the stable syrup obtained in step c) above into dark bottles.

21. The method according to claim 20, CHARACTERIZED by comprising:

b) lower stirring rate to approximately 300 rpm and add polyoxyethylene sorbitan monolaurate with 20 OE, citrus pectin, and then triethanolamine (99%) until the acidity of citrus pectin is neutralized forming a dispersion at approximately pH = 6; c) add then sorbitol (70%), vanilla essence and complete with sterile water up to 100% w/w forming a stable syrup; and

22. The method according to claim 18 or 19, CHARACTERIZED by stirring from step a) is performed at approximately 500 rpm.

23. The method according to claim 18 or 19, CHARACTERIZED by stirring from steps b) and c) is performed at approximately 300 to approximately 350 rpm.

24. The method according to claim 20 or 21 , CHARACTERIZED by stirring from step a) is performed at approximately 400 rpm.

25. The method according to claim 20 or 21 , CHARACTERIZED by stirring from steps b) and c) is performed at approximately 250 to approximately 300 rpm.

26. A method to decrease the levels of free IGF-1 in plasma of individuals who need it using the oral composition according to any of the claims 1 to 17, CHARACTERIZED by comprising administering to such individuals a dosage comprising at least about 250 mg of pectin and approximately 3 mg of papain every at least 12 hours for at least 28 days.

27. The method according to claim 26, CHARACTERIZED by the decrease in plasma free IGF-1 levels is within the range of approximately 50% to approximately 70%.

28. The method according to claim 26 or 27, CHARACTERIZED by the pectin is apple bagasse pectin or citrus pectin.

29. The method according to claim 28, CHARACTERIZED by the pectin used is citrus pectin.

30. The method according to claim 26, CHARACTERIZED by achieving increased levels of plasma transport protein IGFBP-3 which, when binds to IGF-1 , forms a ternary complex with a labile subunit whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life decreasing the levels of free IGF-1.

31. The method according to claim 30, CHARACTERIZED by increased levels of plasma transport protein IGFBP-3 are within the range of approximately 30% to approximately 60%.

32. The method according to any of the claims 26 to 31 , CHARACTERIZED by the at least about 250 mg of pectin and the at least about 3 mg of papain are in dosage forms of soft capsules or each approximately 5 ml_ of syrup.

33. A method to diminish the levels of free IGF-1 in plasma of individuals who need it CHARACTERIZED by comprising treating malignant neoplasms, diabetes, neuropsychiatric disorders, and cardiovascular diseases using the oral composition according to any of the claims 1 to 17, administering to such individuals a dosage comprising at least 250 mg of pectin and at least about 3 mg of papain every at least 12 hours during at least 28 days.

34. The use of pectin and papain together CHARACTERIZED by it is to prepare an oral composition according to any of the claims 1 to 17, useful to diminish the levels of free IGF-1 in plasma of individuals who need it, by means of the administration to such individuals of a dosage comprising at least 250 mg of pectin and at least about 3 mg of papain every at least 12 hours during at least 28 days.

35. The use according to claim 34, CHARACTERIZED by the decrease in plasma free IGF-1 levels is within the range of approximately 50% to approximately 70%.

36. The use according to claim 34 or 35, CHARACTERIZED by the pectin is apple bagasse pectin or citrus pectin.

37. The use according to claim 36, CHARACTERIZED by the pectin used is citrus pectin.

38. The use according to claim 34 or 35, CHARACTERIZED by reaching increased plasma levels of the transport protein IGFBP-3 which, when binds to IGF-1 , forms a ternary complex with a labile subunit whose combined molecular weight and binding affinity allows the growth factor to have an increased half-life decreasing the levels of free IGF-1 .

39. The use according to claim 38, CHARACTERIZED by increased levels of plasma transport protein IGFBP-3 are within the range of approximately 30% to approximately 60%.

40. The use according to any of claims 34 to 39, CHARACTERIZED by the at least about 250 mg of pectin and the at least about 3 mg of papain are in dosage forms of soft capsules or each approximately 5 ml_ of syrup.

41 . The use according to any of the claims 34 to 39, CHARACTERIZED by comprising treating malignant neoplasms, diabetes, neuropsychiatric disorders, and cardiovascular diseases using the oral composition, administering to such individuals a dosage comprising at least 250 mg of pectin and at least 3 mg of papain every 12 hours for at least 28 days.