WO2002015723A1

WO2002015723A1 - Process of preparation and administration of dietary complement

Info

Publication number: WO2002015723A1
Application number: PCT/BR2001/000108
Authority: WO
Inventors: Ana Maria Caetano De Faria; Juscilene Da Silva Menezes; Nelson Monteiro Vaz
Original assignee: Universidade Federal De Minas Gerais
Priority date: 2000-08-25
Filing date: 2001-08-23
Publication date: 2002-02-28
Also published as: AU2001281611A1; BR0004436A

Abstract

The present invention, process of prepare and of administration of dietary complement of amino acids for alimentary regime without proteins and its respective use, is characterized in general terms for the preparation and for the administration of a complement of essential and non essential amino acids to be administered orally together with a diet composed by natural victuals containing balanced amounts of fibers, carbohidrates, lipids, vitamins and mineral salts but without whole proteins (antigens) or with a minimum amount of those proteins. A supplement of vitamins e/ou mineral salts will also be administered together in the case of the selected natural victuals of the alimentary regime do not contain them in approppriate amounts. The present invention is still characterized by its use in the treatment and prevention of diseases, conditions and inflammatory, tumoral and degenerative syndromes, and in congenital and acquired imunodeficiencies in humans and animals.

Description

Process of Preparation and Administration of Dietary Complement

The present invention is characterized by a complement of essential and non essential amino acids containing or not vitamins and/or mineral salts to be administered orally together with an alimentary regime with either a minimum content or without proteins for the treatment of inflammatory, tumoral, and degenerative diseases as well as imunodeficiencies in humans and animals. BACKGROUND OF THE INVENTION

Diets containing amino acids as their sole source of protein are described in the literature as " elementary " diets. The term " elementary " diet is applied for the victuals that contains an elementary source of protein in the form of amino acids and oligopeptides, with small amounts of fat and other nutritients easily digestible such as added minerals and vitamins. In these diets, the components are present as pure chemical entities. The fundamental characteristic of the elementary diets, therefore, is the presence of all the nutritious components (proteins, carbohidrates, lipids, vitamins and mineral salts) in their elementary form. Other diets containing a mixture of components in the elementary and non elementary form have been patented (EP705542-A1, EP100168$-A1, EP1001685-A1, US5189025-A, US4988724-A, US5189025-A, GB2292522-B, WO8300085-A, EP614616-A2, JP61186320-A, JP59016817-A, DE3302008-A, WO8300085-A, EP747395-A1, EP399341, EP764405-A2). Such diets, although containing elementary components and complex components in a non elementary form, can be described as " chemically defined " because they present uniform and reproductible composition with well- known amounts of each component.

The elementary diets were conceived for either parenteral or oral administration in humans and they have been important in the treatment of certain acute pathological conditions. Several applications based on the properties of those diets exist, but extensive research is still required for the use of elementary diets as therapy for chronic diseases. Those applications, in humans, include: post-operative treatment and pre-operative preparation, treatment of gastrointestinal fistule, malabsorption, inflammatory diseases and other diarrhea states, fenilcetonuria and mental deficiency, treatment of patients suffering of cancer, accelerated metabolic states, liver failure and preparation for diagnostic procedures.

Such characteristics and applications of the elementary and chemically defined diets are presented in a wider way in:

1. Winitz, M.; Seedman, D.A.; Graff, J. (1970) Studies in metabolic nutrition employing chemically defined diets. I. Extended feeding of normal human adult evils. Am. J. Clin. Nutr., 23(5): 525-45.

2. Winitz, M. and Adams. R.F. (1971). Chemically defined diets: the new approach to metabolic nutrition. In: K. Lang, W. Fekl and G. Berg, Balanced Nutrition and

Therapy. Thieme, Stuttgart.

3. Russel, R.I. (1975) Elemental diets. Gut, 16: 68-79.

4. Russel, R.I. (1989) Enteral nutrition. Z. Gastroenterol. Suppl. 2: 31-2.

Other chemically defined diets containing amino acids as a source of proteins are suitable for intestinal inflammations, enteropaties, gastro-enterites, intolerance to proteins or to lactose, pancreatic disorders (EP705542-A1), autoimmune and inflammatory diseases, cardiovascular disorders, allergies, neuronal disorders (EP1001685-A1), tumor growth (EP1001685-A1, US5189025-A, US4988724-A, US5189025-A), immunological disorders (GB2292522-B), hepatic problems (WO8300085-A, EP614616-A2, JP61186320-A, JP59016817-A, DE3302008-A, WO8300085-A), renal problems (EP747395-A1, EP399341), nutricionais needs and deficiency in the victuals absorption (EP764405-A2).

However, there are problems in the administration of all the diets described above. They can be enumerated as follows: 1 - the absence of fibers in the diet, leading to disturbances in the peristaltism and in the normal function of the intestine;

2 - its presentation in liquid form that imposes special requirements for its administration such an as solubility;

3 - the described elementary diets contain less than 1% of fat (80% of triglicerids of linoleic acid). Eletrolits and vitamins that are either hidro or liposoluble are added at the minimum levels of daily requirement for humans. They are relatively deficient in zinc and magnesium. Thus, supplements may be required to avoid pathological situations for lack of specific elements in patients using them for a long period;

4 - the high cost of the diets above related due to the fact that they consist chemically of compositions that request the use of many if not all the elements in high purification degree;

5 - a series of collateral effects have been already reported in patients in use of elementary diets: impalatability, nausea, diarrheas, hidroeletrolitic disturbances, hipoprotrombinemia, cutaneous eruptions, hiperglicemia, acinar pancreatic atrophies and aspiration; 6 - the discomfort related to the artificial flavor and to deprivation of natural victuals that accompanies the exclusive administration of chemically defined diets for long lasting treatments;

7 - the solicitation of special cares in the preparation and in the daily handling of chemically formulated diets. All the problems above related hinder the use of the elementary diets and other chemically defined diets for long periods. Therefore, there is a need for a diet complement that could be administered along with an alimentary regime suitable for chronic administration containing no protein. SUMMARY OF THE INVENTION The present invention has as a major goal to overcome the problems and disadvantages already presented for the elementary diets by the usage of a dietary complement characterized by a mixture which is qualitatively and quantitatively well defined, containing or not vitamins and/or mineral salts to be added to an alimentary regime based on natural victuals with minimal protein content. As an important characteristics of the present invention, the dietary complement of amino acids is formulated in such a way that it allows for its usage in different forms: pils, capsules, gels, tablets, emulsions, or other pharmaceutic forms aimed to the oral administration by a mixture with a pharmacologically acceptable vehicle. DETAILED DESCRIPTION OF THE INVENTION In to present invention, the manipulation of the alimentary regime limits to the substitution of whole proteins for amino acids and it drifts from experimental observations, as presented in the examples mentioned to proceed, confirming that the simple absence of protein component is enough to modulate the immunological activity. Therefore, it makes unnecessary the manipulation of other important elements of the normal diet. The increment of vitamins e/ou mineral salts intends to just avoid the lack of those elements in alimentary regimes where the used victuals do not contain them in appropriate concentrations. Thus, the problems related to other chemically defined diets are solved with the present invention:

- appropriate amounts of fibers will be supplied by natural sources of selected victuals;

- the presentation of the present invention in a varied of forms (pills, capsules, gels, tablets, emulsions and other pharmaceutical forms destined to the oral use) of a complement to be added to the natural feeding bestows special requirements for its administration;

- adapted amounts of all the necessary elements to a balanced diet will be supplied by the formulation of a natural alimentary regime also complemented by amino acids in amounts appropriate and, if necessary, still complemented with vitaminais and/or mineral salts;

- the cost of the present preparation will be very low due to the fact of only the amino acids (and, if necessary, vitamins and/or mineral salts) are artificially prepared being the other components of the diet supplied by natural sources; - the reported collateral effects when of the use of elementary diets won't be present during the use of the present preparation because most of the components of the diet will be composed of natural victuals;

- the discomfort related to the administration of the present preparation is minimum because only the amino acids (and, if necessary, vitamins and/or mineral salts) will be administered in artificial preparations;

- the present invention does not require special cares of preparation and of daily handling.

The process of preparation and of admmistration of the complement is characterized by the content of essential and non essential amino acids in the proportion of 10-20% of the total content of the diet, containing or not vitamins and/or mineral salts to be orally administered in the treatment and prevention of inflammatory, tumoral and degenerative diseases, and imunodeficiencias in humans and animals. The process of preparation and administration of the present invention is also characterized by the administration of the other necessary elements to a balanced normal diet that will be present in a regime formulated based on natural victuals without proteins or with minimum amounts of proteins. EXAMPLE 1 - COMPOSITION AND ADMINISTRATION OF THE DIETARY COMPLEMENT

The standard composition of the dietary complement is characterized by a content of essential amino acids and non essential constituting 10-20% of the daily alimentary needs to be used together with an alimentary regime formulated based on natural victuals that do not contain proteins or contain them in minimum amounts. The composition of L-amino acids, expressed in % of the total of amino acids is: histidin (2.3-2.8%), isoleucin (6.1-7.4%) leucin (8.5-10.2%), valin (7.0- 8.4%), lisine (6.6-8.0%), metionin (3.1-3.8%), phenilalanin (5.5-6.6%), treonin (4.8- 5.8%), triptophan (1.7-2.1%), alanin (5.7-6.9%), arginin (6.2-7.5%), aspartic acid (5.9-7.1%), cistein (2.3-2.8%), glutamine (12.9-15.5%), glutamic acid (3.8-4.6%), glicine (3.2-3.9%), prolin (5.0-6.0%), serine (5.4-6.5%) and tirosine (4.0-4.8%). This complement of amino acids will always be used together with the alimentary regime without proteins (or with minimum amounts of proteins). If such na alimentary regime is not enough in the supply of appropriate amounts of vitamins and/or mineral salts, a great composition of vitamins and/or mineral salts will be administered in agreement with the daily nutricional needs. The administration method will be the oral route in the form of pills, or capsules, or gels, or tablets, or emulsions, or other pharmaceutical forms destined to the oral use. EXAMPLE 2 - DATA ON THE EFFECTS OF THE EXPERIMENTAL DIET IN CAMUNDONGOS

The results summarized bellow were obtained from the compariso animals fed a standard balanced diet with animals fed two experimental diets: elementary diet (where all the components are in the elementary form) and experimental diet (where only the proteins are in the elementary form - amino acids). All the diets were administered in the solid form. We observed modifications in important immunological and morphological parameters in both experimental groups as compared to the group of animals fed a standard diet. This fact shows that it is not necessary the manipulation of all the elements of the diet for the production of immunomodulatory effects. The simple substitution of proteins in their antigenic form (intact molecules) for amino acids induces to comparable immunological and morphological modifications. The use of the experimental diet and of the elementary diet in

C57BL/6 mice confirmed some basic properties of these diets, such as the high nutritional effectiveness, since all mice were healthy, with normal weight, and without malnutrition signs.

Morphological studies of the intestinal mucosa of the mice fed the experimental diet and the elementary diet showed that the villi acquired a flat aspect quite different from the rough aspect presented by the animals fed the standard diet. The experimental diet also altered important aspects of the mucosal associated lymphoid tissue in the intestine. It was observed a drastic decrease in the organized mucoal associated lymphoid tissue (Peyer's patches) and in the diffuse mucosal lymphoid tissue (intraepithelial and lamina propria lymphocytes). Besides the local immunological alterations, both diets, the experimental and the elementary, were able to induce also systemic immunological alterations such as: decrease in the immunoglobulin production of IgG and IgA classes, without alteration in the IgM production, suggesting again an immunomodulatory effect rather than a hipogamaglobulinemia. These data is coherent with the decrease observed in the production of pro-inflammatory cytokines (IL-2, IFN-gamma, IL-6). These results suggest a local and systemic immunological anti-inflammatory modulation in mice fed with an antigen-free diet. EXAMPLE 3 - INDICATIONS AND POTENTIAL ADVANTAGES OF THE USE OF THE EXPERIMENTAL DIET

The elaboration of a natural diet without proteins complemented by an equivalent contribution of amino acids presents important immunomodulatory effects, as described in the previous examples. Thus, the dietary complement of amino acids for an alimentary regime without proteins or with minimum amounts of proteins can be applied for the treatment and prevention of pathological conditions where a disregulation in the immunological activity is present including acute and chronic inflammatory diseases, degenerative and tumoral diseases, and in congenital and acquired immunodeficiencies.

The great advantage of the use of this complement associated to a diet without proteins or with minimum amounts of proteins but containing natural victuals is the possibility of the use of the refered complement in the form of pills, or capsules, or gels, or tablets, or emulsions, or other pharmaceutical forms destined to the oral use in humans and animals for short periods and for long periods of time without interfering with the normal conditions of the feeding.

While the present invention has been described in connection with an example, it will be understood that modifications and variations apparent to those ordinary skill in the art are within the scope of the present invention.

Claims

1. Dietary complement of amino acids with the following composition: histidine (2.3-2.8%), isoleucine (6.1-7.4%) leucine (8.5-10.2%), valin (7.0-8.4%), lisine (6.6-8.0%), metionin (3.1-3.8%), phenilalanin (5.5-6.6%), treonin (4.8-5.8%), triptophan (1.7-2.1%), alanin (5.7-6.9%), arginine (6.2-7.5%), aspartic acid (5.9-

7.1%), cistein (2.3-2.8%), glutamine (12.9-15.5%), glutamic acid (3.8-4.6%), glicine (3.2-3.9%), prolin (5.0-6.0%), serine (5.4-6.5%) and tirosine (4.0-4.8%)

2. Dietary complement according to claim 1 characterized by representing 10 to 20% of the caloric content of an alimentary regime formulated with the balanced needs of fibers, carbohidrates, lipids, vitamins, mineral salts supplied by natural victuals that do not contain protein or contain them in minimum amounts.

3. Dietary complement according to claims 1 and 2 characterized by all compounding ingredients being provided by natural victuals that do not contain protein.

4. Dietary complement according to claims 1 and 2 characterized by all compounding ingredients being provided by natural victuals that contain proteins in minimum amounts.

5. Dietary complement according to claim 1 and 2 characterized by the refered complement be dispersed in a pharmacologically acceptable vehicle to be obtained in the form of pils, capsules, gels, emulsions and tablets.

6. Process for treatment and prevention of inflammatory, tumoral and degenerative diseases and immunodeficiencies in humans and animals, by the administration of the complement described in claim 1 to 5 and administered by the oral route.

7. Process of adminstration in humans and animals of a dietary complement of amino acids characterized in claims 1 to 5 in association with an alimentary regime formulated based on natural victuals and in accordance with the daily nutritional needs of proteins.

8. Process of preparation of a dietary complement of amino acids characterized by the mixture of purified amino acids as described in claim 1 added, at room temperature, to the appropriate vehicle for the chosen pharmaceutic form (either pil, or tablet, or capsule, or emulsion or gel) together with an alimentary regime formulated based on natural victuals and in accordance with daily caloric needs but containing minimal amounts of protein complemented or not by vitamins and/or mineral salts if the selected natural victuals do not contain them in the appropriate concentrations.