Abstract:
Colostrum solutions, their formulations and a method of making the solutions are presented. These solutions could be used in situations where the mother is not able to naturally provide colostrum to an infant.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims the benefit of provisional application Ser. No. 61/146,260 filed Jan. 21, 2009 for Infant Formula Compositions for Neonates Lacking Mother&#39;s Own Colostrum and Method of Making, which is incorporated in this application as if fully set forth herein. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    1. Field of the Invention 
         [0003]    The present invention relates to synthetic infant formulas and specifically, to synthetic colostrum for initial feeding of neonates. 
         [0004]    2. Description of the Related Art 
         [0005]    Colostrum is nature&#39;s transition food between the non-caloric amniotic fluid swallowed by the fetus while in the womb and the mature human milk feedings which begin about one week after birth. Colostrum is a preparatory feeding substance. It has a composition that is considerably different from mature milk. Transition between colostrum and mature milk begins about three days after birth and is complete in about one week. 
         [0006]    Table 1 below comparatively illustrates the constituent parts of mature milk as compared to natural colostrum. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
                 TABLE 1 
               
               
                   
                   
               
               
                   
                 Constituent per Liter 
                 Mature Milk 
                 Colostrum (average) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Protein 
                 10 
                 g 
                 23 
                 g 
               
               
                   
                 Fat 
                 40 
                 g 
                 10-30 
                 g 
               
               
                   
                 Carbohydrate 
                 72 
                 g 
                 53 
                 g 
               
               
                   
                 (lactose) 
               
               
                   
                 Calcium 
                 280 
                 mg 
                 230 
                 mg 
               
               
                   
                 Phosphorus 
                 140 
                 mg 
                 150 
                 mg 
               
               
                   
                 Sodium 
                 180 
                 mg 
                 480 
                 mg 
               
               
                   
                 Potassium 
                 530 
                 mg 
                 740 
                 mg 
               
               
                   
                 Chloride 
                 420 
                 mg 
                 750 
                 mg 
               
               
                   
                 Zinc 
                 1200 
                 ug 
                 5000 
                 ug 
               
               
                   
                 Vitamin E 
                 3150 
                 ug 
                 12800 
                 ug 
               
               
                   
                 Lactoferrin 
                 1700 
                 mg 
                 3300 
                 mg 
               
               
                   
                 Vitamin B12 
                 260 
                 mg 
                 1000 
                 mg 
               
               
                   
                   
               
             
          
         
       
     
         [0007]    As can be seen from the chart, compared with natural mature milk, colostrum is much higher in concentrations of protein, sodium, potassium chloride and particularly minerals and vitamins. Yet, it is much lower in fat. 
         [0008]    Commercially artificial formulas available for the mature milk feedings of neonates whose mothers do not provide human milk are based on bovine milk. There is no artificial formulation of colostrum available. Without artificial colostrum, many babies admitted to an NICU receive nothing by mouth for several days until either their mother produces colostrum or until an artificial formula or banked human milk feeding is begun. This period of receiving no nourishment by mouth is unnatural and may result in temporary disuse atrophy of small bowel mucosal villi, leading to feeding intolerance when feedings are begun. 
         [0009]    In order to render mature milk or artificial formula more appropriate and better tolerated for ill or premature neonates, it has been proposed to dilute mature milk. However, from Table 1 above, it is clear that diluted milk does not approximate colostrum. Dilution reduces the fat content, but colostrum actually has more protein and certain minerals and vitamins than mature milk. Therefore, diluting mature milk or formula to make it better tolerated during the first days of life does not meet the unique physiologic needs of newborn infants in the first days. 
         [0010]    It is, therefore imperative that a synthetic variety of colostrum be made available for use by neonates. 
       SUMMARY OF THE INVENTION 
       [0011]    The present invention contemplates synthetic colostrum solutions that could be used in situations for which the mother is not able to naturally provide colostrum to an infant Furthermore, more advanced colostrum formulations containing human milk and other relevant proteins, as well as human milk fat is contemplated. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0012]      FIG. 1  is a graph showing pre-feeding gastric residuals. 
       
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
       [0013]    The artificial formulations of the present invention which are intended to simulate human colostrum are intended as a first food for neonates admitted to neonatal intensive care units. Feeding can begin in small quantities (10-30 mL/k/d) on the first day of life and be used in small volume feedings until the mother produces colostrum that can be used to feed the baby or until a mature milk substitute such as artificial formula or pasteurized banked human milk, begins. Further, in addition to neonatal intensive care units, it is proposed that these artificial colostrums can as well be used extensively in a baby nursery for well babies during the first and second day of life feeding when the mother chooses not to breastfeed or is unable to do so. 
         [0014]    By utilizing these artificial formulations, the baby is being fed a substance that is well tolerated and physiological before artificial formulas based on cow&#39;s milk proteins are introduced into the infant&#39;s diet. This practice can be far better tolerated than the present practice of initiating feeding with mature milk formulas. The failure of human milk banks to produce colostrum as a product can be due to the fact that it is made in any given mother in very small quantities and for only a few days. Furthermore, it is felt that colostrum is so valuable to a mother&#39;s own baby that the ethics of harvesting colostrum are questionable. 
         [0015]    In an embodiment, the present invention proposes a simple synthetic colostrum. An example of suitable constituents and amounts in the formulation of synthetic colostrum is shown below in Table 2. Further, a specific example of a formulation of synthetic colostrum is shown below in Table 3. 
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
             
             
               
                 Sterile Water 
                 Sufficient to make 1 
                 liter 
               
               
                 CARBOHYDRATE 
               
               
                 Lactose 
                 47.7-58.3 
                 grams 
               
               
                 PROTEIN 
               
               
                 Amino Acids 
                 20.7-25.3 
                 grams 
               
               
                 FAT 
               
               
                 Cholesterol 
                 270-330 
                 milligrams 
               
               
                 Fatty Acids 
                 18-22 
                 grams 
               
               
                 VITAMINS 
               
               
                 MVI Ped 
                 27-33 
                 milliliter 
               
               
                 Vitamin E 
                 11520-14080 
                 micrograms 
               
               
                 Vitamin B12 
                 1800-2200 
                 nanograms 
               
               
                 B Carotene 
                 1008-1232 
                 micrograms 
               
               
                 MINERALS 
               
               
                 Sodium Acetate 
                 432-528 
                 milligrams Sodium 
               
               
                 Potassium Chloride 
                 666-814 
                 milligrams Potassium 
               
               
                 Calcium Gluconate 
                 207-253 
                 milligrams Calcium 
               
               
                 Magnesium Sulfate 
                 31.5-38.5 
                 milligrams Magnesium 
               
               
                 TRACE ELEMENTS 
               
               
                 Zinc 
                 4500-5500 
                 micrograms 
               
               
                 Copper 
                 1800-2200 
                 micrograms 
               
               
                 Manganese 
                 450-550 
                 micrograms 
               
               
                 Iodine 
                 450-550 
                 micrograms 
               
               
                 Energy (kcal) 
                 453.6-554.4 
                 kcal 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
               
               
               
               
             
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Constituents 
                 Source 
                 Constituent/Liter 
               
               
                   
               
             
             
               
                 Sterile Water 
                 Sterile water USP 
                 Q.S. 
               
               
                 CARBOHYDRATE 
               
             
          
           
               
                 Lactose 
                 Lactose USP (solution) 
                 53 
                 g 
               
               
                 PROTEIN 
               
               
                 Amino Acids 
                 Trophamine 
                 23 
                 g 
               
               
                 FAT 
               
               
                 Cholesterol 
                 Cholesterol USP 
                 300 
                 mg 
               
             
          
           
               
                 Fatty acids (linolenic, 
                 Microlipid (50%) 
                 20 g (40 mL) 
               
               
                 oleic, palmitic, 
               
               
                 linolenic, stearic) 
               
               
                 VITAMINS 
               
             
          
           
               
                 Vitamins (MVI-PED) 
                 MVI-PED 
                 30 
                 mL 
               
               
                 Vitamin E 
                   
                 12800 
                 ug 
               
               
                 Vitamin B12 
                   
                 2000 
                 ng 
               
               
                 β Carotene 
                   
                 1120 
                 ug 
               
               
                 MINERALS 
               
               
                 Sodium acetate 
                   
                 480 
                 mg Na 
               
               
                 Potassium chloride 
                   
                 740 
                 mg K 
               
               
                 Calcium phosphate 
                   
                 230 
                 mg Ca 
               
               
                 Magnesium sulfate 
                   
                 35 
                 mg Mg 
               
               
                 TRACE ELEMENTS 
                 Stock Solution 
                 5 
                 mL 
               
               
                 Zinc 
                 ″ 
                 5000 
                 ug 
               
               
                 Copper 
                 ″ 
                 2000 
                 ug 
               
               
                 Manganese 
                 ″ 
                 500 
                 ug 
               
               
                 Iodine 
                 ″ 
                 500 
                 ug 
               
               
                 ENERGY (kcal) 
                   
                 504 
               
               
                   
               
             
          
         
       
     
         [0016]    These Tables 2 and 3 illustrate sterile isotonic solutions that simulate human colostrum. The solutions are completely synthetic containing no intact proteins or peptides. Although they are an incomplete colostrum, these formulations are still tolerable by the neonate. Further, in an embodiment, natural human colostrum can be simulated by fewer constituents than presented in Tables 2 and 3. For example, a simpler solution can consist of only sterile water, carbohydrate, protein, and fat constituents without adding vitamins, minerals, and trace elements. 
         [0017]    In an embodiment, the present invention also contemplates producing a colostrum formulation that can mix with human milk and/or relevant constituents including, but not limited to, lactoferrin, IgA, alpha lactalbumin and human milk fat. An example of suitable constituents and amounts in the formulation of a synthetic colostrum formulation to mix with human milk is shown below in Table 4. Further, an example of a specific formulation that can be mixed with a natural human milk solution is shown below in Table 5. 
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
             
             
               
                 Sterile Water 
                 Sufficient to make 1 
                 liter 
               
               
                 CARBOHYDRATE 
               
               
                 Lactose 
                 0-58.3 
                 grams 
               
               
                 PROTEIN 
               
               
                 Amino Acids 
                 20.7-25.3 
                 grams 
               
               
                 FAT 
               
               
                 No Added Fat 
               
               
                 VITAMINS 
               
               
                 MVI Ped 
                 27-33 
                 milliliter 
               
               
                 Vitamin E 
                 11520-14080 
                 micrograms 
               
               
                 Vitamin B12 
                 1800-2200 
                 nanograms 
               
               
                 MINERALS 
               
               
                 Sodium Acetate 
                 432-528 
                 milligrams Sodium 
               
               
                 Potassium Chloride 
                 666-814 
                 milligrams Potassium 
               
               
                 Calcium Gluconate 
                 207-253 
                 milligrams Calcium 
               
               
                 Magnesium Sulfate 
                 31.5-38.5 
                 milligrams Magnesium 
               
               
                 TRACE ELEMENTS 
               
               
                 Zinc 
                 4500-5500 
                 micrograms 
               
               
                 Copper 
                 1800-2200 
                 micrograms 
               
               
                 Manganese 
                 450-550 
                 micrograms 
               
               
                 Iodine 
                 450-550 
                 micrograms 
               
               
                 Energy (kcal) 
                 453.6-554.4 
                 kcal 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                 Constituents 
                 Source 
                 Constituent/Liter 
               
               
                   
               
             
             
               
                 Sterile Water 
                 Sterile water USP 
                 Q.S. 
               
             
          
           
               
                 CARBOHYDRATE 
                   
                 53 
                 g 
               
               
                 Lactose 
                 Lactose USP (solution) 
                 27 
                 g 
               
               
                 PROTEIN 
                   
                 23 
                 g 
               
               
                 Amino Acids 
                 Trophamine 
                 17 
                 g 
               
               
                 FAT 
                   
                 2 
                 g 
               
               
                 No added fat 
                 No added fat 
               
               
                 VITAMINS 
               
               
                 Vitamins (MVI-PED) 
                 MVI-PED 
                 30 
                 mL 
               
               
                 Vitamin E 
                   
                 12800 
                 ug 
               
               
                 Vitamin B12 
                   
                 2000 
                 ng 
               
               
                 MINERALS 
               
               
                 Sodium acetate 
                   
                 qs to total 480 
                 mg Na 
               
               
                 Potassium chloride 
                   
                 qs to total 740 
                 mg K 
               
               
                 TRACE ELEMENTS 
                 Stock Solution 
                 5 
                 mL 
               
               
                 Zinc 
                 ″ 
                 5000 
                 ug 
               
               
                 Copper 
                 ″ 
                 2000 
                 ug 
               
               
                 Manganese 
                 ″ 
                 500 
                 ug 
               
               
                 Iodine 
                 ″ 
                 500 
                 ug 
               
               
                 ENERGY (kcal) 
                   
                 480 
               
               
                   
               
             
          
         
       
     
         [0018]    Since a separate milk solution is also required in the solutions of Tables 4 and 5, these formulations can be more expensive to produce than the solutions of Table 2 and 3. However, they can also provide significant advantages. For example, the solution exemplified in Table 5 is produced by starting with 500 mL of human milk to which is added Lactose USP, Trophamine, MVI, sodium acetate, potassium chloride and a trace element stock solution containing zinc, cooper, manganese and iodine, for example, and sterile water USP to make up a one liter volume. With the more expensive milk constituent, the solution exemplified in Table 5 contains human milk proteins and human milk fat. It can also contain human lactoferrin, human alpha lactalbumin, human casein, and human IgA. As a result, this solution of Table 5 can be a more complete simulation of natural colostrum, and can also contain more immunological properties than the solution exemplified in Table 3. Further, fewer constituents can be formulated than presented in Tables 4 and 5. For example, a simpler solution can consist of only sterile water, carbohydrate, and protein without adding vitamins, minerals, and trace elements. 
         [0019]    All solutions of the present invention can be made in the same manner that solutions are made using stock constituents. The solutions are not a biological product, i.e. they are not a product of human milk or animal milk. Rather, they are chemical compositions of basic nutritionals and USP constituents. An example of a formula and instructions for compounding an artificial colostrum formulation is below in Table 6. 
         [0000]    
       
         
               
               
               
             
               
             
               
               
               
               
             
               
             
               
               
               
               
             
           
               
                 TABLE 6 
               
               
                   
               
               
                   
                 Amount 
                   
               
               
                 Ingredient 
                 (mg/mcg/g/ml) 
                 Amount (ml volume and concentration used) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Items pumped in the clean room 
               
             
          
           
               
                 Trophamine 10% 
                 5 
                 gm 
                 (50 ml * 10%) 
               
               
                 Phytonadione 
                 0.6 
                 mg 
                 (0.3 ml * 2 mg/ml) 
               
               
                 (Vit K) 
               
               
                 Folic Acid 
               
               
                 Sodium Acetate 
                 166 
                 mg Na 
                 (3.6 ml * Na Acetate 2 mEq/ml) 
               
               
                 Sodium Phosphate 
                 74 
                 mg Na 
                 (0.8 ml * Na Phos 4 mEq/ml) 
               
               
                 Potassium 
                 370 
                 mg K 
                 (4.75 ml * KCl 2 mEq/ml) 
               
               
                 Chloride 
               
               
                 Calcium 
                 115 
                 mg Ca 
                 (12.35 ml * Ca Gluc 10%) 
               
               
                 Gluconate 
               
               
                 Magnesium 
                 17.5 
                 mg Mag 
                 (0.355 ml * Mg Sulfate 50%) 
               
               
                 Sulfate 
               
               
                 Zinc 
                 2.5 
                 mg 
                 (2.5 ml * Zinc Sulfate (or Chloride) 1 mg/ml) 
               
               
                 Copper 
                 1 
                 mg 
                 (2.5 ml * Cupric chloride 0.4 mg/ml) 
               
               
                 Manganese 
                 2.5 
                 mg 
                 (2.5 ml * Manganese Chloride 0.1 mg/ml) 
               
               
                 Chromium 
               
               
                 Selenium 
               
               
                 Iodine 
                 250 
                 mcg 
                 (2.5 ml * Iodine 100 mcg/ml) 
               
               
                 Sterile Water 
                 100 
                 ml 
                 (100 ml) 
               
             
          
           
               
                 Items weighed/measured and added after items pumped in clean room 
               
             
          
           
               
                 Lactose 
                 26.5 
                 grams 
                 (Stored with other compounding items) 
               
               
                 Cholesterol NF 
                 150 
                 mg 
                 (Stored in refrigerator by unit dose area) 
               
               
                 Microlipids 50% 
                 5 
                 gm 
                 10 ml of Microlipids 50% 
               
               
                 Poly-Vi-Sol 
                 1.5 
                 ml 
               
               
                 Sterile Water 
                 qsad 500 
                 ml 
               
               
                   
               
               
                 Mixing directions: 
               
               
                 1. Pump or add liquid ingredients in the IV room. (Note: DO NOT clamp the pump port of the IV bag.) 
               
               
                 2. Weigh out all powder ingredients. 
               
               
                 3. Open and drain the contents of a 500 ml bottle of sterile water for irrigation. (Save the water in a clean container for step #7.) 
               
               
                 4. Add all of the liquid ingredients, except for the Microlipids and sterile water, to the empty container. 
               
               
                 5. Add the powder ingredients to the same container. 
               
               
                 6. Add the Microlipids. 
               
               
                 7. Add sterile water to a total volume of 500 ml. 
               
               
                 8. Add 0.5 ml of Sodium Hydroxide 50% to bring final pH to approximately 6.7 (use pH paper or Multistix). 
               
               
                 9. Label container and give a 24 hour refrigerated expiration date. 
               
             
          
         
       
     
         [0020]    The solutions of the present invention are feasible to feed to patients. When mother&#39;s own colostrum is not available for a neonatal intensive care unit (NICU) patient, the standard practice is to initiate feedings with one of the bovine-based infant formulas. Intolerance of the first day of bovine-based feedings is common. Yet, the artificial colostrum solution of Table 3 was found to be well tolerated during feedings that were judged by signs of feeding intolerance; emesis, diarrhea, bloating, visible bowel loops, and large pre-feeding gastric residual volumes. 
         [0021]    26 NICU patients who had no mother&#39;s own colostrum, but who were otherwise ready to begin enteral feedings were tested. The solution of Table 3 was administered in a volume of 2.5 mL/kg every 3 hours for the first eight feedings (24 hrs) for each patient. Demographics of the 26 NICU patients that were fed the solution of Table 3 for their first eight feedings are listed in Table 7. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 NICU patients whose mother&#39;s own colostrum was not available, and were fed 
               
               
                 the artificial colostrum of Table 3 for the first eight feedings. 
               
             
          
           
               
                   
                 BW 
                 Gestational 
                   
                   
                 Day of life Sylostrum 
               
               
                 N 
                 (grams) 
                 Age (weeks) 
                 Race/Ethnicity 
                 Gender 
                 feedings were begun 
               
               
                   
               
               
                 26 
                 2135 ± 605 
                 33.7 ± 3.6 
                 White 88% 
                 Male 38% 
                 2.0 ± 0.3 
               
               
                   
                   
                   
                 Black 8% 
               
               
                   
                   
                   
                 Hispanic 4% 
               
               
                   
               
             
          
         
       
     
         [0022]    All 26 patients were fed the artificial colostrum solution of Table 3 as planned, for the first day of feedings. As shown in Table 8, 202 of the 208 feedings that were planned (26 patients X 8 feedings/patient) were given. Six (3%) were not given. One feeding was postponed because of emesis that occurred following endotracheal intubation. One feeding was postponed (a separate neonate) for three hours because of increased abdominal girth. Four feedings were postponed for nonspecified reasons 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 Feasibility and tolerance of feedings of artificial 
               
               
                 colostrum solution of Table 3. 
               
             
          
           
               
                   
                 Percent of the planned 
                 Percent of the 
                 Percent of the feedings 
               
               
                   
                 feedings that were 
                 feedings 
                 held because of increased 
               
               
                   
                 actually given as 
                 held because 
                 abdominal girth or visible 
               
               
                 N 
                 planned 
                 of emesis 
                 bowel loops 
               
               
                   
               
               
                 26 
                 97.2 ± 7.3% 
                 1/208* 
                 1/208** 
               
               
                   
                 (202/208) 
               
               
                   
               
               
                 *One feeding was postponed because of emesis that occurred following endotracheal intubation (one patient). 
               
               
                 **One feeding was postponed on one patient, but was given three hours later when the examination was normal. 
               
             
          
         
       
     
         [0023]    For these NICU patients,  FIG. 1  shows the amount of the pre-feeding gastric residual did not increase significantly after any of the eight artificial colostrum feedings or after the eight subsequent milk feedings. Prior to the first feedings, about 1 mL/kg body weight of fluid was detected in the stomach. Accordingly, among this group of 26 NICU patients who had no mother&#39;s own colostrum, it was feasible to administer the artificial colostrum solution of Table 3, 2.5 mL/kg every three hours for the first eight feedings. The solution was well tolerated, with fewer than 3% of the planned feedings withheld. 
         [0024]    Prefeeding gastric residual volumes measured in NICU patients before their first artificial colostrum of Table 3 feeding was given and before each of their subsequent 16 feedings (two days). 
         [0025]    In the foregoing specification, the invention has been described with reference to specific embodiments. However, it will be appreciated that various modifications and changes can be made without departing from the scope of the present invention as set forth in the claims below. The specification and figures are to be regarded in an illustrative manner, rather than a restrictive one, and all such modifications are intended to be included within the scope of present invention. Accordingly, the scope of the invention should be determined by the appended claims and their legal equivalents, rather than by the examples given above. For example, the steps recited in any of the method or process claims may be executed in any order and are not limited to the order presented in the claims.