MXPA00007181A - Process of improving the stability of vitamin d in a nutritional product containing hydrolyzed protein and product produced thereby - Google Patents
Process of improving the stability of vitamin d in a nutritional product containing hydrolyzed protein and product produced therebyInfo
- Publication number
- MXPA00007181A MXPA00007181A MXPA/A/2000/007181A MXPA00007181A MXPA00007181A MX PA00007181 A MXPA00007181 A MX PA00007181A MX PA00007181 A MXPA00007181 A MX PA00007181A MX PA00007181 A MXPA00007181 A MX PA00007181A
- Authority
- MX
- Mexico
- Prior art keywords
- protein
- per gram
- methionine
- vitamin
- concentration
- Prior art date
Links
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- 235000001892 vitamin D2 Nutrition 0.000 description 1
- 239000011653 vitamin D2 Substances 0.000 description 1
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Abstract
A liquid enteral nutritional hypoallergenic formula is disclosed. The formula contains carbohydrates, lipids, protein hyrolysates, free amino acids, vitamins, minerals and L-methionine as an added component at therapeutically effective levels to provide a liquid dietary formula with improved Vitamin D stability and acceptable Protein Efficiency Ratio.
Description
PROCESS TO IMPROVE THE STABILITY OF VITAMIN D IN A
NUTRITIONAL PRODUCT CONTAINING HYDROLYZED PROTEIN AND
PRODUCT PRODUCED THROUGH THE SAME
TECHNICAL FIELD This invention relates to a method for improving the stability of Vitamin D in a liquid nut product comprising hydrolyzed proteins and / or free amino acids. The process comprises the addition of methiomna to the nut product to ensure nutptional sufficiency and reduced complementation or Removed from Cystine The invention also relates to nut-made products made through the inventive process
BACKGROUND OF THE INVENTION Some adults and infants have food allergies that include sensitivity to intact protein or poor protein digestion. These individuals require a special nut formula, such as a hypoallergenic formula, to meet their dietary needs. Hypoallergenic formulas, which are sometimes referred to as elemental formulas, they are characterized in that they usually contain hydrolysates, such as, soy protein hydrolyzate, casein hydrolyzate, whey protein hydrolyzate or a combination of animal and vegetable protein hydrolysates as the main source of ammo nitrogen. The hypoallergenic formulas also they can use only free amino acids as the source of amino nitrogen. Protein hydrolysates comprise short peptide fragments and / or
free amino acids instead of the intact protein found, for example, in formulas based on cow's milk and isolated from soy protein. These fragments of short peptides and free amino acids have been found to be less immunogenic and allergenic than intact proteins. they experience adverse reactions to intact protein, they are often able to tolerate liquid nut products based on hydrolysates. Normal sources of hydrolyzed protein include casein, whey, rice, soy, and beef collagen. Alimentum® is one of such hypoallergenic nut formulations that is manufactured by Ross. Products Division of Abbott Laboratories, Columbus, Ohio Ahmentum® is a nutically complete formula containing a extensively hydrogenated casein, which is approximately 60% by weight of free amino acids, with the rest being small peptides. Such predigestion virtually eliminates allergenicity. h idrolizado of protein, the concentration of a number of amino acids, such as tpptophan and tyrosine, is significantly reduced In this way the hydrolyzate fortification with these "lost" amino acids is necessary to restore the nutpcional sufficiency Although cystma is not an essential amino acid products such as Alimentum® have been traditionally fortified with cystine, in order to mimic the amino acid profile of breast milk. In this way, in addition to the casein that has been enzymatically hydrolyzed and treated with charcoal, Alimentum has added L-cystine dihydrochloride , L-tyrosma, L-tpptophan, taurine and L-carnitine Pregestimil® and Nutramigen®,
which are hypoallergenic infantile nutpcionales manufactured by Mead Johnson Division of Bpstol Meyers Squibb of Evansville, Indiana, are supplemented with L-cystine, L-tpptophan, L-tyrosine taurine and L-carnitine All these pediatric hypoallergenic formulas are also fortified with Vitamin D at a level above 45 IU (label claim) for 142 ml or 100 calories In addition to the protein hydrolyzate, most of the hypoallergenic, nutritionally balanced formulas contain carbohydrates, lipids, vitamins and minerals. These hypoallergenic formulas are used to feed infants , children and adults, who have allergies or sensitivities to intact protein, and are frequently used medically in the treatment of cystic fibrosis, chronic diarrhea, galactosemia, small bowel resection, steatorrhea and malnutrition of protein-calopa Advera®, a complete nutpcional, specialized for the dietetic management of people with infection of H IV or AI DS, AlitraQ®, an elemental nutpcional, specialized with glutamine for metabolically stressed patients, and Perative®, a specialized liquid nutritional for the dietary management of patients metabolically stressed, they contain all hydrolyzed protein and / or free amino acids as their source of nitrogen. All of these products are manufactured and distributed by Ross Products Division of Abbott Laboratories, Columbus, Ohio All of these products also contain Vitamin D and are susceptible to degradation of Vitamin D when they are in liquid form, due to the presence of protein hydrolysates and free amino acids
The beneficial qualities of Vitamin D are well documented and accepted For example, Vitamin D regulates the level of calcium in the body and is responsible for depositing calcium and phosphorus in the bone from the blood Very little Vitamin D can cause soft bones, weakness muscle, poor growth, bone fractures and secondary hyperthyroidism Although vitamin supplements can be taken as a tablet, Vitamin D is generally easier to obtain from the diet, especially a diet containing foods enriched in Vitamin D The most common biologically active forms of Vitamin D are previtamins D2 and D3 and vitamins D2 and D3. Previtamin D2 and vitamin D2 are produced from ergosterol and are biologically active in humans, cattle, pigs and other mammals. Previtamin D3 and Vitamin D3 are biologically active. and are produced on the skin of many animals following the irradiation (ie, sun exposure) of 7- dehydrocholesterol The other isomeric forms of Vitamin D do not show significant biological activity The isomepzacion of Vitamin D bio-available to inactive forms occurs in solution The stability of Vitamin D in a nutpcional matrix is dependent on the number of factors For example, light, high temperatures and iodine catalyze the conversion of the biologically active forms of Vitamin D to inactive forms are excellent sources of Vitamin D liquid nutpcionales products that are fortified with Vitamin D With regard to fortification with Vitamin D and infant formula, Vitamin levels D in
children's products are federally regulated in the United States under the Infant Formula Act (IFA) (Children's formulas act). Nutritional products containing levels above or below those exposed in the I FA can not be offered legally for sale. Hypoallergenic formulas are found a greater problem with respect to the stability of Vitamin D Vitamin D undergoes significant degradation in protein hydrolyzate formulas and / or formulas containing free amino acids In fact, research has shown that the more hydrodase the protein is, the greater is the degradation of Vitamin D Specifically, the inherent and fortified sources of free or combined cysteine and cystine are capable of forming the tillo free radical (in the presence of a free radical initiator, such as oxygen or peroxides) that isomepza Vitamin D to non-bioavailable forms These free radical reactions also make to Vitamin D more susceptible to oxidation that converts Vitamin D to non-bioavailable forms This ability to isomepzar Vitamin D to non-bioavailable forms through a free radical reaction involving the radical of Tyrium is true for all sulfur compounds present as a thiol (such as cysteine) or as a disulfide (such as cystine) The reaction also occurs with peptides containing cysteine or disulfide-linked peptides, but is generally not observed with intact proteins due to unobstructed obstructions Reactions do not occur in Sulfur containing molecules, in which the sulfur atom is not bound to hydrogen or sulfur, due to the inability of these compounds to easily form the free radical of
Therefore, sulfur compounds, such as methionine salts and esters, cystathionine, S-methylcystin and cysteine sulfonate, will not induce the degradation of Vitamin D In view of the problems with the degradation of Vitamin D in nut products. liquids containing hydrolyzed protein and / or free amino acids, some products are over-fortified with Vitamin D The over-fortification is used to satisfy the claim of the label for Vitamin D content over the shelf life of the product However, as mentioned before, there are acceptable upper limits of Vitamin D concentration, because too much Vitamin D can cause hypercalcemia, hypercalciupa, stones in the urinary tract, extraskeletal calcifications and malfunction of the kidneys and other organs In a similar way, if the concentration of Vitamin D falls below a certain limit due to degradation, the product must be removed from sale to the public The costs associated with the replacement, shipping and global monitoring of the level of Vitamin D in liquid nutptional products are significant There is a need in the industry today to enhance the stability of Vitamin D in a liquid hypoallergenic formula. U.S. Patent No. 4,836,957 to Nemoto, et al, discloses a preparation containing an active form of Vitamin D3 that is stabilized by incorporation of an amino acid that is not containing neither a sulfur atom nor an amino acid group in its structure. , neither an acidic amino acid, nor a salt of an amino acid basic
This patent does not concern the stability of Vitamin D in liquid nut formulations containing protein hydrolysates and / or free amino acids. U.S. Patents 5, 382,439 and 5,456, 926 to Hili, et al, describe a method for improving the stability of the protein. Vitamin D in liquid nut products containing hydrogenated protein or free amino acids These patents show that Vitamin C should be added to a concentration exceeding 300 mg per liter and that cystine should be added to the liquid nut product after the completion of a treatment Preliminary heat Although these patents describe methods that solve the problem of Vitamin D stability in a hypoallergenic product, they are not entirely satisfactory. Thus, it is clear that there is a need for a method to improve the stability of Vitamin D in the presence of protein hydrolysates and / or free amino acids without adversely affect the nutritional quality of the formula
DESCRIPTION OF THE INVENTION In general, this invention relates to the discovery that the stability of Vitamin D in liquid nut products can be dramatically improved by eliminating or limiting cystine fortification without sacrificing nutptional sufficiency, provided that methionine is used to provide the nutrients. sulfur-containing amino acid requirements when assessing that animal growth is met The present invention
it also provides an improved hypoallergenic formula that minimizes the need for over-fortification with Vitamin D and provides an excellent protein quality for normal growth in humans
Thus, a method for improving the stability of Vitamin D in a liquid nut product is discounted, wherein said nut product comprises Vitamin D and a source of amino nitrogen selected from free amino acids, hydrolyzed protein and mixtures thereof, said method comprising the addition of L-cystine to said product at a level not to exceed 7 mg (in addition to inherent levels) per gram of protein and the addition of L-methionine to said product at a level of at least 9.0 mg (in addition to inherent levels) per gram of protein In a more preferred embodiment, the liquid nut product is a infant formula Still in a more preferred embodiment, less than two mg of cystine are added to the nut product per gram of total protein and at least 1 2 mg of L-methionine are added per gram of total protein. Very preferably, no more than 0 5 mg per gram of L-cystine and at least 14 mg of L-methionine are added per gram of total protein Still in a more preferred embodiment, no L-cystma is added to the nut product and at least 1.5 grams of L-methion is added. A liquid product is also described comprising an amino nitrogen source selected from the group consisting of hydrolyzed proteins, free amino acids and mixtures thereof, Vitamin D and L-methionine as a substance added at a concentration of at least 9.0 mg per gram of protein
From another perspective, the invention can be seen and implemented in terms of the total content of the amino acids containing sulfur, methionine, cystine and cysteine. The protein hydrolyzate used in the hypoallergenic formulas will contain inherent levels of methyomine, cystine and cysteine. For example, the Intact casein inherently has 30 mg of methionine per gram of protein and four mg of cystine (cystine plus cysteine) per gram of protein. As used herein and in the claims, the levels associated with cystine will be understood as meaning of the sum of cystine plus cysteine This is a result of analytical chemistry In contrast, the casein hydrolyzate used in Alimentum has an inherent level of methiomine of approximately 26 mg per gram of protein and approximately six mg of cystine per gram of protein to realize the benefits of Improved stability of Vitam ina D and adequate growth, the inventors have determined that at least 45 mg (320 micro-moles (μM)) of amino acids containing sulfur (cystine, methionine and cysteine) per gram of protein are present in the inventive formula of protein hydrolyzate and amino acid supplementation. At least 34 mg of the 45 mg of sulfur-containing amino acids should be methionine. Thus, a hydroxide containing 28 mg of methionine per gram of protein and seven mg of cystine per gram of protein (inherent levels) will be fortified with at least six mg of methionine (34-28 = 6) per gram of protein and may, but not necessarily, be further fortified with four mg of cyst (6 + 28 + 7 + 4 = 45)
In this manner, a method for improving the stability of Vitamin D in an aqueous liquid product is also disclosed, wherein said nut product comprises Vitamin D and a source of amino nitrogen selected from hydrogenated protein, free amino acids and mixtures of the same, said method comprising the steps of a) providing a liquid nut product containing Vitamin D, b) adding L-methionine to said product so that the total (inherently more complementary) level of L-methiomna is at least 34 mg per gram of protein and the addition of at least one amino acid selected from the group consisting of lysine, tpptophan, tyrosine, taurine and L-carnitma
There is also a method for improving the stability of Vitamin D in a liquid nut product, wherein said nut product comprises Vitamin D and an amino nitrogen source selected from hydrolyzed protein, free amino acids and mixtures thereof, said method comprising the addition of L-methionine to achieve a total level of L-methiomna of at least 34 mg per gram of protein and the addition of at least one amino acid selected from the group consisting of cystine, cysteine and mixtures thereof to achieve a concentration of less 45 mg of sulfur-containing amino acids per gram of protein An improved hypoallergenic enteral nutidional comprising lipid, carbohydrate, vitamin D and an amino nitrogen source is also described, the improvement characterized because the source of amino nitrogen is selected from hydrolyzed protein, free amino acids and mixtures thereof, wherein the sum of all the amino acids contained or sulfur is
at least 50 mg per gram of protein and the level of methionine is at least 40 mg per gram of protein. In a more preferred embodiment, the level of methynom is at least 42 mg per gram of protein and the level of cystine is less than 1 2 mg per gram of protein In an even more preferred embodiment, the formula comprises at least 43 mg of metiomna (inherent plus complemented) per gram of protein and less than ten mg of cystine (inherent plus complemented) per gram of protein In a modality most preferred, the formula comprises less than eight mg of cystine per gram of protein and at least 42 mg of methionine per gram of protein. This invention also relates to an enteral nut with an
Improved PER comprising an amino nitrogen source, the improvement characterized in that the source of amino nitrogen is selected from the hydrolyzed protein, free amino acids and mixtures thereof, and wherein the concentration of L-methionine is at least 34 mg per gram of In yet another aspect of the present invention, the inventors have determined that an improved hypoallergenic formula comprises Vitamin D and at least 34 mg of total methionine (inherent plus fortification) per gram of protein and less than 12 mg of total cystine ( inherent plus fortification) per gram of protein Still in a more preferred embodiment, the formula comprises at least 40 mg of methionine per gram of protein and less than ten mg of cystine In a highly preferred embodiment, the formula comprises at least 42 mg of methionine per gram of protein and less than eight mg of cystine per gram of protein
In a similar manner, a process for the production of an improved hypoallergenic enteral formula comprising protein hydrolysates is described, said process comprising the steps of supplementing said formula with Vitamin D and free methionine to achieve a total concentration (inherent plus fortification) of methioin of at least 34 mg per gram of protein, more preferably at least 40 mg per gram of protein, and most preferably at least 42 mg per gram of protein The process may further comprise the addition of free cystine to achieve a total concentration (inherent more fortification) of cyst not exceeding 12 mg per gram of protein The hydrolyzed protein used in the present invention can be any edible source of protein, such as, animal proteins (ie, meat and fish), cereal (ie, rice and corn) and vegetable proteins (ie, soy). More specifically, the protein source may be milk proteins, such as casein and whey The most preferred source of protein for hydrolysis is casein In addition to the hydrodase protein, the nutptional product of this invention may additionally contain free amino acids other than L-methiomna. Any amino acid may be added to the formula, however, it should be Thus, in addition to L-methionine, the nutptional according to this invention is fortified, preferably, with tpptophan, tyrosine, taurine and L-carnitine. In addition, the addition of cystine and / or cysteine is avoided. an enteral hypoallergenic nutpcional comprising, based on the total calories of the nutpcional,
about 30-65% carbohydrates, about 30-60% lipids, about 5-20% of an amino nitrogen source selected from hydrodase protein, free amino acids and mixtures thereof, and about 400 to 1,000 IU per liter of Vitamin D, the improvement characterized in that said nutptional comprises L-methionine as a component added at a concentration of at least 9 mg per gram of protein. In a more preferred embodiment, the L-methiomna is at a concentration of at least 9 mg per gram of protein In a more preferred embodiment, the L-methiomna is at a concentration of at least 12 mg per gram of protein, and most preferably at a concentration of at least 14 mg per gram of protein The hypoallergenic nut in accordance with this invention may also contain as an added component, an amino acid selected from lysine, tpptophan, tyrosine, taurine, L-carnitine and mixtures thereof. provides a method to improve the stability of Vitamin D in liquid nut products having hydrolyzed protein and / or free amino acids as the primary source of amino nitrogen. The method is extremely easy to practice, very reliable and does not compromise the nutritional quality of the formula. The primary objective of the invention is directed to infant formulas, the invention is also applicable to other liquid nut products that use hydrolyzed proteins and / or amino acids as a source of amino nitrogen. The formula can take the form of a ready-to-eat product, a concentrate or a powder
In still another embodiment, this invention relates to a method for improving the stability of Vitamin D in a liquid nut product containing hydrolyzed protein and / or free amino acids as the amino nitrogen source, the method comprising the step of adding L- metionma to said liquid nutptional product at a concentration of L-methiomna added of at least 9 mg per gram of protein. An improved liquid nut formula with stability of intensified Vitamin D and a source of amino nitrogen which provides acceptable growth, is also described. According to the methods described above. Other objects and advantages of this invention will be apparent from the following description and the appended claims. As used herein and in the claims, the total protein upon which the level of amino acid fortification is based , is determined through the Kjeldahl method for the determination of nit total nitrogen The principle of the Kjeldahl method is the conversion of substances containing nitrogen to ammonium sulfate when boiling with sulfuric acid in the presence of a catalyst, usually copper sulphate Potassium sulphate is added to raise the boiling point The mixture is alkaline then and the ammonia is distilled to standard acid Details of this technique can be found in numerous textbooks on chemical analysis or practical biochemistry The nitrogen value is converted to grams of protein by multiplying grams of nitrogen per 6 25
As used herein and in the claims, the levels of added methionine or any other amino acid are based on the total protein content, including the added amino acids. For example, if one formula contains ten grams of protein per liter, the ten grams is the sum of all the proteins, protein fragments and free amino acids and a fortification level of 1 5 mg per gram of protein includes the 1 5 mg in each gram of protein The cystine or dicysteine (C6H12N20,? S2) has the structure chemistry
H2C - S - S - CH2 I I H2N - CH HC - NH2 COOH COOH
Cystine consists of two molecules of cysteine (cystine produces cysteine on a reduction). In this way, due to the two sulfur atoms, one mole of cystine provides two moles of amino acid equivalents containing sulfur. Cystine is particularly abundant in proteins. of skeletal, connective, hair and animal wool tissues Methionine or 1 -am? no-3-met? lmercaptobutyric acid (C5Hn N02S) has the chemical structure
CH3 - S - CH2 - CH2 - CH - COOH I NH,
Methionine is one of the natural amino acids that contain sulfur and is present in small amounts in protein hydrolysis products compared to most other amino acids. It is an essential constituent of mammalian foods and is particularly important since this and choline are the only compounds in the diet that are known to take part in mediating reactions. As used herein and in the claims, the term "methiomna" includes the salts and esters of methionine, cystationma, s-methylcystin and sulfonate Also as used herein and in the claims, it will be understood that all declared amino acids, including cystine and methionine, are in the L- or levo-rotary form.
DETAILED DESCRIPTION OF THE INVENTION The hypoallergenic formula according to the present invention is made by mixing carbohydrates, fupids and a protein hydrolyzate, homogenizing the mixture to a stable emulsion, adding complementary free amino acids and sterilizing the product in the range of pH from about 6 to about 7 The protein hydrolyzate of the invention may be any suitable protein hydrolyzate used in a nut-formula, such as, soy protein hydrolyzate, cereal grain protein hydrolyzate, casein hydrolyzate, hydrolyzate whey protein, animal and vegetable protein hydrolyzate and mixtures thereof The protein hydrolyzate of the hypoallergenic formula of the invention is,
preferably, a soy protein hydrolyzate or a casein hydrolyzate comprising short peptides and free amino acids The immunogenicity of the formula of the present invention is highly dependent on the degree of hydrolysis of the selected protein. To ensure the hypoallergenicity of the formula, the protein hydrolyzate it should be extensively hydrolyzed to produce very short peptides and free amino acids. This is important because it is known that free amino acids and di- and tp-peptides are absorbed through the small intestine without any digestive interruption. Preferably, peptides are avoided. of high molecular weight because they are more allergenic and cause precipitation and destabilization of the liquid nutptional emulsion. In a preferred embodiment, the hydrolyzate of the protein of the invention contains a high percentage of low molecular weight peptide fragments. In general, any technique known can be used to produce the protein hydrolyzate Preferably, the protein is hydrolyzed to such an extent that the ratio of amino nitrogen (AN) of the free amino acids in the total nitrogen hydrolyzate (TN) of the intact protein, protein fragments and amino acids free, ranges from about 0 3 AN to 1 0 TN to about 0 8 AN to 1 0 TN Such hydrolysis generally produces hydrolysates with the following representative molecular weight distribution
The hypoallergenic formula can also use only free amino acids as the source of amino nitrogen or they can be more hydrolyzed than the one given above. An aspect of this invention resides in the discovery that the protein source will be supplemented with significant levels of methion and only sparingly, if at all, with cystine and it will still be nutically adequate for growth. The formula can be fortified with other free amino acids, such as, L-tpptophan, L-tyrosine, L-arginma, L-taupna and L-carnitma. The total caloric value of the hydroprotein of protein and free amino acid mixtures supplemented in the hypoallergenic formula can vary from about 8% to about 20% of the total calories of the formula, and is preferably in the range from about 10% to about 14% of the Total calories Although it is known that the presence of cystine in a hypoallergenic nutpcional drink increases After the degradation of Vitamin D, a replacement is required to ensure that proper growth and maintenance of protein is achieved. One aspect of the invention resides in the discovery that methiomine can be added to the formula
It is a measure of the quality of protein using laboratory rats. The inventors have found that the replacement of cystine with methionine in micro-moles (μM) of amino acid equivalents containing sulfur (eg, two moles of methionine for each mole of cystine), results in a formula that provides adequate nutrition for growth (amino nitrogen), has an excellent PER and dramatically improves the stability of Vitamin D in liquid nutritional
Analytical method for Vitamin D In order to determine whether the method of the invention is effective in reducing the degradation of vitamin D, it was necessary to determine in a precise manner the concentration of bio-active Vitamin D in the formula The technique used by the inventors to quantify Vitamin D was a modification of the method published by Sertl and Molitor, Journal of the Association of Official Analytical Chismists, Volume 68, Number 2, 177-182 (1988) The method consists in saponifying the sample, extracting Saponified sample, subjecting the extract to preliminary liquid chromatography, cleaning and subjecting the clean extract to quantitative liquid chromatography. Details of these analytical procedures can be found in US Pat. No. 5,456,926 to Hill, et al.
Under the First Formula Act (I FA) in the United States, there are certain maximum and minimum levels assigned to Vitamin D in the formula
For example, the upper limit for a formula of 20 calories per 28 4 ml is 676 IU per liter, or 1 00 IU per 1 00 calories. The liquid nutptional product is usually over-fortified, so that time zero (time when the container is ready for sale) the concentration of Vitamin D has fallen to the acceptable range. During the shelf life of the product, the concentration of Vitamin D may fall below the acceptable minimum and in that case, the product would have to be reclaimed or exchanged According to the Infant Formula Act in the United States, the minimum acceptable level of Vitamin D is 40 IU per 100 calories or 270 IU per liter for a infant formula containing 20 calories per 28 4 ml
EXAMPLE I Study of PER This experiment was conducted to evaluate the intact casein PER, casein hydroids and casein hydrolysates fortified with methiomna at two levels, and with lysine and / or tpptophan. The investigation was conducted according to the AOAC Method 960 48, AOAC Official Methods of Analysis, 15th edition, 1990 There were two control groups used in this experiment, one was the casein-based diet (intact protein) having the composition given in the official method of AOAC and the second was based on a non-fortified casein hydrolyzate that was used in Alimentum® (none shown in Table I) A total of six experimental diets were prepared that were based on the casein hydrolyzate with levels and types of fortification vanished
Table I shows the fortification of each diet based on milligrams of amino acid added per 1 g of total protein (nitrogen per 6 25)
Table I Experimental Diets Basis of casein hydrolyzate plus milligram of amino acid per 1 0 gram of total protein
* MET = methionine LYS = lysine hydrochloride TRP = tpptophan
Each diet was virtually identical in caloric content, source and distribution of calories from carbohydrate and fat, and in macro- and micro-nutrients. The Control diet of casein hydrolyzate contained an inherent total of approximately 27-28 mg of methionine per gram of protein Diets 1 to 4 contained 32-33 mg of methionine as actually analyzed (most complementary inherent) per gram of protein, and Diets 5 and 6 contained 34 mg of methionine per gram of protein as actually analyzed Sprague-Dawley weaned male rats between 21 and 23 days of age with an initial weight between 40 and 60 were used in this experiment.
grams The animals were placed in test cages for an acclimatization period of three to four days. During this time, the rats received a standard rat food diet. After acclimation, at 1 0 rats per group they were assigned a diet of Control or Experimental Rats were fed their assigned diet and water ad libitum Animals were weighed at the start of the study and every week during the study period of four weeks Dietary intake was measured and PER was calculated by the method given in the PER procedure of AOAC, 15th ed Method 960 48, 1 990 Table II shows the data generated in this experiment For each diet, the average weight gain per animal, the average amount of protein consumed and the PER are reported. for each diet
Table I I PER for Control and Experimental Diets
* Values that share the same superscripts do not differ significantly (values p> 0 05), Tukey Multiple Comparison Procedure
The data indicate that the supplementation of the casein hydrolyzate with methynan base at a total level of 34 mg per gram of protein level significantly improves the PER of the protein system (Diets 5 and 6) Surprisingly, no response was evident Upon complementation with lysine and / or tpptophan, it appears that the complementation of a casein hydroxide with methionine can greatly enhance the growth efficiency of the protein system. This interesting result forms an aspect of the present invention.
EXAMPLE II Stability of commercially available Vitamin D Alimentum® served as the control in this experiment containing a casein hydrolyzate fortified with the amino acids L-cystine (1.1 mg per gram of protein), L-tpptophan and L-tyrosine. Experimental contained the same casein hydrolyzate but was supplemented with 1 5 or 9 2 mg of methionine (depending on the total protein concentration in the formula) instead of the 1 1 mg of cystine per gram of total protein in the Control product Table III shows the Control and Experimental products
Table l l l Product formulations
average value of 20 lots
Vitamin D levels were determined during storage of shelf life in product maintained at room temperature. The results are shown in Table IV
Table IV Concentrations of Vitamin D (IU / 1) after storage at room temperature
Claims for Vitam ina label D - 304 I U / I NT - unproven
From Table IV, it is evident that the Experimental products according to the invention experienced less degradation of Vitamin D than the Control product Table V exposes the loss of Vitamin D from processing and over a study period of 12 months. The total loss in IU per liter and% of original fortification is also shown in Table V
Table V Vitamin D loss (IU / 1) Loss from O to 1 2 months
It is quite evident from Table V that the hypoallergenic products using the present invention, (Samples llll) are significantly less likely to fall outside the acceptable ranges of Vitamin D during storage than the Control product used. in the methods of the prior art
EXAMPLE III Study of PER A formula according to this invention was analyzed by PER substantially in the manner set out in Example I Groups of 10 rats each, were fed a diet for 28 days according to the invention or a formula based on casein using Method 960 48 from AOAC, AOA C Official Methods of Analysis, 5th edition, 1990 Every seven days, the rats were weighed and their feed intake recorded. At the end of 28 days, the total weight gain was calculated. and the
protein composition of the two groups These values were used to calculate the PER The composition of each diet is shown in Table VI
Table IV Composition of diets
* mg / g of total protein ** addition of cystine before the first heat treatment *** addition of cystine subsequent to the first heat treatment
+ added com dihidrocloruro de cistma
The intact casein contained inherent levels of methionine ranging from 26-30 mg per gram of protein and cystine to
approximately 4.0 mg per gram of protein The casein hydrolyzate contained approximately 26 mg of methiomna per gram of protein and approximately 4.0 mg of cystine per gram of protein. Diets 7 and 8 were identical except that cystine was added before, or Subsequent to, a heat treatment that was used during the manufacture of infant formula The Control Diet and the 7-10 Diets contained the same mixture of edible oils at approximately the same percentage of total calories (34 2 to 39 8%) The carbohydrate was the same in all diets and was from approximately 51 0 to 56% of the total calories. As all the components of the diets were similar, except for the amino nitrogen source, the differences in the growth of the animals can attributed to the effectiveness of the protein system to support growth. Thus, the higher the PER, in theory, the better the protein system will be. exposes the PER for each diet and the percentage increase over the Control
Table VI l PER values
The results of this experiment indicate that the protein system according to the present invention (Diets 9 and 10) has a significantly higher protein efficiency ratio (Tukey Student's Range Test per variable) than the conventional protein system (Control and Diets 7 and 8), where the fortification of cystine Diets 9 and 10 was used, which were fortified with methionine (39 6 and 44 mg of total methionine per gram of total protein) and fortification of cystine dihydrochloride decreased or none (total cystine of 4 0 and 10 4 mg per gram of protein) proved to be the highest in the study. Other diets where methionine fortification did not occur, proved to be significantly lower than diets fortified with methionine. was very similar to the commercially available Alimentum® product today (30 mg of total methionine and 1 5 mg of total cystine per gram of protein) and had a PER of only 2 8 This experiment supports an aspect of the present invention, which is that the increased fortification of amino acids containing sulfur different from cystma, has a beneficial effect on the growth of animals. This aspect, in combination with the reduction or elimination of cystine fortification, results in a hypoallergenic nut product with enhanced Vitamin D stability and a protein system for acceptable growth As a result of this work, an improved hypoallergenic nut formula with acceptable protein quality and Vitamin D stability has been developed
EXAMPLE IV Clinical Trial As the protein quality and stability of Vitamin D of a hypoallergenic nut formula have been demonstrated in accordance with the present invention, the following clinical study was undertaken to demonstrate efficacy in human infants. The purpose of the study was to investigate whether to replace Methionine fortification by cystine or modifying protein level and amino acid fortification would have some effect on the growth of healthy male infants. Control formula was commercially available Alimentum®
Diet 1 1 was Alimentum® with increased levels of protein and methionine, while cystine fortification was reduced Diet 1 2 was Alimentum® with metiomine fortification and without cystine fortification The stability of Vitamin D in this study was also measured Other biochemical responses of infants, such as plasma albumin, were also evaluated, urea nitrogen and plasma amino acids This clinical trial was a 16-week, blind, randomized, controlled growth study in male infants. Shortly after birth, the researchers were contacted by parents of eligible infants. The study was explained and asked the parents of the children to sign an Informed Consent Form On Day One of enrollment (SD1), infants were assigned to a feeding group by an investigator, usually a pediatrician, and were seen again by the doctor at the weeks four, eight and 1 6 (± three days)
after enrollment Anthropometric measurements were obtained at the entrance to the study and at subsequent visits. The Control and Experimental formulas were prepared in a similar manner Table VI II shows the target addition levels of cystine, methionine, tyrosine and tpptofano for the Control and the Diets 1 1 and 12
TABLE VI I I Obietive addition ratios (mg per grams of protein)
Table IX sets out the analyzed levels of protein, Vitamin D, Vitamin C, cystine, methionine, tyrosine and tpptophan for the Control and Experimental diets Table IX also contains data on the selected amino acid content of representative human breast milk and a intact casein representative
TABLE XIX Analyzed level of several components
* - average of two lots ** - values calculated from the Pediatric Nutrition Handbook, American Academy of Pediatrics, 2nd ed 1985
The equipment and procedures used to prepare the Control and Experimental formulas are conventional and well known to those skilled in the art. All the study foods were supplied as ready-to-eat (RTF) in 907 ml cans and provided 20 kcal per 28 4 ml All formulas met or exceeded nutrient levels as recommended by the Committee on Nutrition of the American Academy of Pediatrics (1985) and the Infant Formula Act (1980) and amendments Subsequent (1986)
The formula volume, incidence of spit, vomit and stool patterns were recorded in diaries completed by the parents during the three days just before the study visits at four, eight and sixteen weeks Caloric and protein intakes were calculated based on the formula volume and nutrient composition shots of the formula with which they were fed. The weight, length and circumference of the head at birth were obtained from the hospital records. Weight, length and height were measured. head circumference to SD1 and at each study visit (four, eight and 16 weeks) by the same examiner at each site, according to the procedures in the Guide to Growth Assessment of Infants in Clinical Studies growth of infants in clinical studies) provided by Ross Products Division, Abbott Laboratories Weights of naked bodies were obtained using an electronic balance ica Length tables were used to obtain the lengths, measuring tapes were used to obtain the circumferences of the head and the upper arm, while calipers were used to obtain the thickness of the skin fold in the triceps. Approximately 2 cc of infants' blood by venipuncture by a certified technician, nurse or doctor at 4 and 16 weeks of age for determination of plasma albumin, urea nitrogen and plasma amino acids The sample was taken 1 50 to 1 80 minutes after of the start of the last feeding The plasma was frozen at -70 ° C until it was analyzed
The three feeding groups were evaluated for their ability to compare to the input. The anthropometers were analyzed at birth and at the entrance using ANOVA. The gestational age and age at SD1 were compared using ANOVA in the classified data. The Apgar records of five minutes were analyzed. and ethnicity using a Fisher's Exact test. The evaluation of feeding effects was performed using ANOVA of Repeated Measurements. They were also analyzed separately at each visit using ANOVA. The ordinal variables were compared separately at each time using ANOVA or Cochran Tablecloth tests. -Haenszel Categorical variables were analyzed at each time using Fisher's exact test. The location of the study (site) was used as a blocking factor in the ANOVA models. The transformations in the classification were used in the analysis of the percentage of tolerance and stool variables, predominant faecal consistency, volume taking and blood biochemistry The stool consistency of the average range was also analyzed using the untransformed data All tests were performed using a 5% significance level The primary analysis was done in the subset of completers only An "attempt to treat" analysis was made including data available in all subjects as a secondary analysis
Subjects A total of 73 infants successfully completed the study (23 in
Control 25 in Diet 1 1, 25 in Diet 1 2) A total of 27 infants were considered to be treatment failures due to food intolerance in the study (1 3 in Control, 6 in Diet 1 1, 8 in the diet
12) and 22 infants were considered protocol failures No statistically significant differences were observed between groups for gestational convenience One infant was considered small for gestational age, 88 infants were appropriate for gestational age and 33 infants were considered large by gestational age No Significant differences were observed between the groups by age at SD1, gestational age or five-minute Apgar record. The average age of infants at the beginning of the study varied from 1 8 to 2 3 days (range 0 to five days of age). Average gestational age at birth vain from 39 3 to 39 4 weeks
Anthropometric measurements No statistically significant differences were observed in weight, length or circumference at birth or in their respective registers NCHS Z No statistically significant differences in weight, length or head circumference or their respective NCHS Z records were observed to SD1 or to four, eight or 16 weeks Most importantly, no statistically significant differences were observed between the groups in weight gains, adjusted weight gains, length gains or head circumference gains to four,
Eight or 16 weeks In addition, no statistically significant differences were observed between groups for a total area of the upper arm, muscle area of the upper arm, fat area of the upper arm or fat index of the arm to SD1, five, eight or 16 weeks or in gains of these to four, eight or 16 weeks The study also revealed that there were no significant differences between groups in the average number of foods per day, the average volume of formula intake , adjusted average volume of formula intake, adjusted caloric intake or caloric efficiency at four or eight weeks The adjusted average protein intakes extracted through the visits differed significantly (P <0 01) between the feeding groups Infants fed Diet 1 2 had significantly higher average adjusted protein intakes than infants fed Diet 1 1 to four weeks (P < 0 01) and mean adjusted protein intakes significantly higher than infants fed Diet 1 1 and Control at eight weeks At 16 weeks, infants fed Diet 12 had a significantly higher volume of formula intakes, adjusted volume of higher formula intakes, and adjusted caloric intakes than those infants fed Diet 1 1 (P < 0 05) In addition, at 1 6 weeks, infants fed Diet 12 had significantly higher adjusted protein intakes than infants fed Diet 1 1 or Control (P <0 01). Infants fed Diet 1 1 had significantly greater caloric efficiency at 16 weeks than infants fed diet
Diet 12 (P <0 05) No differences were observed in the percentage of foods with spit and / or vomiting between the groups during the study
There were no significant differences between the groups in the number of stools per day during the study. In addition, no significant differences were observed between the groups in the percentage of stools that were watery, loose / with mucus or formed at each visit during the study. However, infants fed Diet 12 had significantly higher plasma urea nitrogen concentrations than infants fed Diet 1 1 and Control at four weeks. For data extracted through the visits, plasma methionine concentrations differed significantly between the food groups (P <; 0 01) Infants fed Diet 12 had significantly higher plasma concentrations of asparagine, proline, valine, isoleucine, leucine and tyrosine than infants fed with Control at four weeks Infants fed diets 1 1 and 1 2 had serum methionine concentrations significantly higher than infants fed control at four weeks. When the only data from successful completers were analyzed, only plasma methionine differences were statistically significant. At 16 days, the only significant difference observed was that the infants fed Diet 1 1 had a significantly higher plasma methionipal level than infants fed Control
Conclusion The inventors of the present have formulated the theory that amioacid methionine could be used to fortify a hypoallergenic formula in place of cystine to ensure that the sulfur containing amino acid requirements were met. This study was conducted to determine the effects of system modification. of protein of a hypoallergenic formula in the growth and biochemical response of infants The results of this study confirmed that replacing methionine with cystine did not result in any alteration in the growth of healthy male infants during the first four months, compared with infants fed with Control formula, which was Alimentum® commercially available The results of the study also indicate that there was no advantage in feeding the infants with a formula containing increased protein with methionine fortification and without cystine fortification. All the groups grew in a remarkably similar way during the study and when comparing the weights of these infants with the weights of infants fed Similac® With Iron (a childhood formula of intact protein marketed by Ross Products Division of Abbott Laboratories, Columbus, Ohio) in recent studies, The weights were also very similar. Very importantly, no adverse effects were observed in the group of infants fed a methionine-fortified product.
Industrial applicability The results of these experiments demonstrate that the hypoallergenic enteral formula of this invention is effective in providing adequate growth without the need to over-fortify with Vitamin D. The medical community is constantly seeking nutritional formulas that benefit the infant / patient. invention can clearly meet that need The manufacture of the formula uses conventional equipment and can be easily achieved In addition, the discoveries of the invention have application to other nut products that use hydrolyzed proteins and / or free amino acids and need an increased level of Vitamin D stability Although the formula and method for making said formula described herein constitute a preferred embodiment of this invention, it will be understood that the invention is not limited to this precise formulation or method, and that changes thereto can be made without departing from it. of the scope of the invention as defined in the appended claims
Claims (1)
- CLAIMS 1 A method for improving the stability of Vitamin D in a liquid nut product, wherein said nut product comprises Vitamin D and an amino nitrogen source selected from free amino acids, hydrolyzed protein and mixtures thereof, said method comprising the addition of L-cystine to said product at a level not to exceed 7 mg per gram of protein and the addition of L-methiomna to said product at a level of at least 9 mg per gram of protein 2 The method according to the claim 1, wherein said nut product is a infant formula 3 The method according to claim 1, wherein said hydrodase protein is selected from hydrolyzed casein, whey, soy, milk, rice, corn, vegetable protein, meat, fish and mixtures thereof 4 The method according to claim 1, wherein said L-cyst is added to said product at a level that does not exceed 2 mg per gram of protein and said L-methylene s added to said product at a level of at least 1 2 mg per gram of protein The method according to claim 1, wherein said L-cystine is added to said product at a level not exceeding 0 5 mg per gram of protein and said L-methionine is added to said product at a level of at least 14 mg per gram of protein 6 A liquid hypoallergenic enteral nutical comprising, based on the total calories of the nutpcional, approximately 30 to 65% carbohydrates, approximately 30 to 60% lipids, approximately 5 20% of an amino nitrogen source selected from hydrolyzed protein, free amino acids and mixtures thereof, and approximately 400 to 1,000 IU per liter of Vitamin D, characterized by the improvement because said excipient comprises L-methion as an added component at a concentration of at least 9.0 mg per gram of protein and the concentration of L-cystma, inherent and added, does not exceed 7.0 mg per gram of protein 7. The nutptional according to claim 6, wherein said L-methionine as an added component, it is at a concentration of at least 1 2 mg per gram of protein 8 The nutritional according to claim 6, wherein said L-methionine as an added component is at a concentration of at least 14 mg per gram of protein 9 The nutpcional according to claim 6, wherein said nutpcional further comprises, as an added component, an amino acid selected from lysine, tptophan, tyrosine, taurine, L-carnitine and mixtures thereof A liquid nut product comprising a) an amino nitrogen source selected from the group consisting of hydrolyzed proteins, free amino acids and mixtures thereof, b) Vitamin D, c) L-methionine as a substance added at a concentration of at least 9 mg per gram of protein, and d) L-cystine is present at a concentration not exceeding 7 mg per gram of protein based on both inherent and complementary L-cystine. The liquid nutrient according to claim 10, wherein said hydrolyzed protein is selected from casein. hydrolyzed, whey, soy, milk, rice, corn, vegetable protein, meat, fish and mixtures thereof 1 2 A method for improving the stability of Vitamin D in a liquid nut product containing hydrogenated protein as an amino source nitrogen, the method comprising the steps of a) providing a liquid nut product containing Vitamin D, b) adding L-methionine to said product, so that the total concentration of L-methionine is at least 34 mg per gram of protein, and ) adding at least one amino acid selected from the group consisting of lysine, tpptophan, tyrosine, taurine and L-carnitine 1 3 The method according to claim 12, wherein said pr Hydrogenated Othene is hydrolyzed casein 14 The method according to claim 12, wherein said L-methiomna is added so that the concentration of L-methionine is at least 38 mg per gram of protein 1 5 The method according to claim 12, wherein said L-methionine is added so that the total concentration of L-methionine is at least 40 mg per gram of protein. A method for improving the stability of Vitamin D in a liquid nut product, wherein said product nutpcional comprises Vitamin D and an amino acid source selected from hydrolyzed protein, free amino acids and mixtures thereof, said method comprising the addition of L-methionine to achieve a total L-methionine level of at least 34 mg per gram of protein and the addition of at least one amino acid selected from the group consisting of cystine, cysteine and mixtures thereof, to achieve a concentration of at least 45 mg of sulfur-containing amino acids per gram of protein The method according to claim 16, wherein the sum of all those amino acids containing sulfur is at least 50 mg per gram of protein and the methionine level is at least 40 mg per gram of protein. with claim 16, wherein the total level of said methionine is at least 42 mg per gram of protein 19 An enteral nut with an improved protein efficiency ratio (PER) comprising a source of ammo nitrogen, characterized the improvement because the source of ammo nitrogen is selected from hydrolyzed protein, free amino acids and mixtures thereof, and wherein the The concentration of L-methionine is at least 34 mg per gram of protein. A process for the production of an improved hypoallergenic enteral formula comprising protein hydrates, said process comprising the step of supplementing said formula with L-methionine to a total concentration. of at least 34 mg of methionine per gram of protein The enteral nutpoint according to claim 1 9, wherein said L-methionine is at a concentration of at least 38 mg per gram of enteral nut protein according to claim 1, wherein said L-methionine is at a concentration of at least 40 mg per gram of protein 23 The process according to claim 20, wherein said L-methiomna is at a concentration of at least 38 mg per gram of protein 24 The process according to claim 20 , wherein said L-methionine is at a concentration of at least 40 mg per gram of protein. An enteral formula made according to the process that accords with claim 20.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/072,165 | 1998-01-22 |
Publications (1)
Publication Number | Publication Date |
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MXPA00007181A true MXPA00007181A (en) | 2001-07-31 |
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