Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-05-12
2001-10-23
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S547000, C514S078000
Reexamination Certificate
active
06306908
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to enteral formulas that contain long-chain polyunsaturated fatty acids (PUFAs) and to a process for making such enteral compositions. More particularly, the present invention relates to enteral compositions which provide long chain PUFAs arachidonic acid (AA) and docosahexaenoic acid (DHA) essentially free of cholesterol and may be derived from egg yolk lipids. Long chain PUFAs provided from egg yolk are predominantly in a phospholipid form. The process of making such a composition provides improved organoleptic and stability properties.
BACKGROUND OF THE INVENTION
Long chain PUFAs in enteral formulas or compositions have been the subject of diverse literature. For example, U.S. Pat. No. 4,670,285 (“Clandinin”) discloses a specific fat blend suitable for use in infant formulas. More specifically, the Clandinin fat blend contains at least one C
20
or C
22
&ohgr;-6 fatty acid and a C
20
or C
22
&ohgr;-3 fatty acid. These fatty acids are disclosed as being at certain, defined amounts to avoid causing harmful effects to an infant fed the fat blend. The C
20
or C
22
&ohgr;-6 fatty acids are present in a total amount of about 0.13 to 5.6% by weight of all fatty acids in the product. The C
20
or C
22
&ohgr;-3 fatty acid, if present, are included in a total amount of about 0.013 to 3.33% by weight of all fatty acids in the product. Clandinin discloses the use of egg lipids to supply the &ohgr;-6 and &ohgr;-3 fatty acids; however, the egg lipid used by Clandinin also contains high levels of cholesterol. Further, this reference teaches the use of 75 to 95 parts by wt. of egg yolk lipid with the remainder of the oil being coconut oil or soybean oil. The nomenclature used by Clandinin for fatty acids will be utilized herein.
WO 93/20717 discloses an infant formula which contains no more than sub-irritant amounts of free long chain (C
16
-C
22
) fatty acids and triglycerides. This application also discloses that providing lower alkyl esters, such as ethyl esters, of such fatty acids in infant formula essentially eliminates the tendency of the free fatty acid to damage the intestinal epithelium of the infant, but permits absorption and processing of the fatty acid moiety.
U.S. Pat. No. 4,918,063 to Lichtenberger discloses compositions containing unique mixtures of phospholipids and neutral lipids for the prevention or treatment of ulcers and inflammatory bowel disease. This patent discloses mixtures of saturated or unsaturated phospholipids, together with saturated or unsaturated triglycerides and/or sterols, as providing ulcer protective efficacy in experimental animal models. This patent also teaches the inclusion of polyvalent cations or antioxidants to the lipid mixture to enhance activity.
International Publication No. WO 96/10922 to Kohn et al. discloses a fat mixture for infant formula characterized in that arachidonic acid and docosahexaenoic acid are present in the fat mixture in the form of phospholipids.
European Patent Application 0 376 628 B1 to Tomarelli discloses an all vegetable oil fat composition which utilizes randomized palm oil or randomized palm olein oil as the sole palmitic acid oil source. It is also disclosed that the all vegetable oil fat compositions are particularly suited for use in infant formulas for pre-term (or low birth weight) infants. The preterm fat compositions of the Tomarelli application include medium chain triglycerides (MCT's) with a randomized palmitic acid oil, lauric acid oil, an oleic acid oil and a linoleic acid oil.
Although the references discussed above have made important contributions, there remains a need for infant formulas that contain egg phospholipids as a source of long chain PUFAs in concentrations appropriate for nutrition. A further need remains for methods of preparing enteral formulas containing egg phospholipids such that the formulas have acceptable organoleptic properties. Such compositions have particular application in infant formula for term and/or preterm infants, whose needs for long chain PUFAs are established for the proper neural development and for development of visual acuity. In addition, there may be a protective effect on the gut.
Necrotizing enterocolitis (NEC) is a serious problem in infants having birth weights of less than about 1500 grams. Despite almost three (3) decades of study, the precise etiology and pathophysiology of NEC remains unclear. NEC is a life-threatening disease characterized by ischemic necrosis of the involved alimentary tract structures and pneumatosis intestipalis, which often results in the perforation of the bowel. A pre-term infant with NEC presents a clinical picture of thermal instability, lethargy, gastric retention, vomiting, abdominal distension, gross or occult blood in the stools and radiographic evidence of pneumatosis intestinalis, air in the portal veins or pneumoperitoneum Apnea spells, shock and sclerema rapidly appear and death is common.
Numerous authors have made varied observations and posited factors influencing this malady. (Nue,
Pediatr. Clin. North. Am
., April, 1996, 43(2): 409-32). The following observations and factors are exemplary:
Flageole et al., Ngecrofizing Enterocolitts of the Newborn, Review for the Clinician. Union-Med-Can. 1991 Sep-Oct; 120(5): 334-8, suggest the pathogenesis of NEC includes mesenteric ischemia, gastrointestinal immaturity, enteral feedings and even possibly infection;
Caplan et al., Role of Platelet Activating Factor and Tumor Necrosis Factor-Alpha in Neonatal Necrotizing Enterocolitis,
Journal of Pediatrics
, June, 1990, 960-964, report platelet activating factor and tumor necrosis factor-alpha are elevated in patients with NEC;
Kliegman et al., Clostridia as Pathogens in Neonatal Necrotizing Enterocolitis,
The Journal of Pediatrics
, August, 1979, 287-289, reports the isolation of Clostridia perfringens from children with neonatal NEC;
Ostertag et al., Early Enteral Feeding Does Not Affect the Incidence of Necrotzing Enterocorfibs,
Pediatrics
, Vol. 77, No. 3, March 1986, 275-280, reports that dilute, early enteral calories do not adversely affect the incidence of NEC;
Bell et al., Neonatal Necrottzing Enterocolitis,
Annals of Surgery
, Vol. 187, January 1978, No. 1, 1-7, suggests the use of combination antimicrobial therapy for the treatment of infants with NEC;
Eyal et al., Necrotizing Enterocolitis in the Very Low Birth Weight Infant: Expressed Breast Milk Feeding Compared with Parenteral Feeding,
Archives of Disease in Childhood
, 1982, 57, 274-276 reports that the incidence of NEC in low birth weight infants was reduced by delaying the initiation of enteral feeding.
Finer et al., Vitamin E and Necrotizing Enterocolitis, Pediatrics, Vol. 73, No. 3, March 1984 suggests that administration of vitamin E to reduce the incidence of severe sequelae from retrolental fibroplasia may be associated with an increased incidence of NEC.
Brown et al., Preventing Necrotizing Enterocolitis in Neonates,
JAMA
, Nov. 24, 1978, Vol. 240, No. 22, 2452-2454 reports that NEC can be virtually eliminated by the use of a slowly progressive feeding regimen.
Kosloske, Pathogenesis and Prevention of Necrotizing Enterocolitls: A Hypothesis Based on Personal Observation and a Review of the Literature,
Pediatrics
, Vol. 74, No. 6, December 1984, 1086-1092, hypothesizes that NEC occurs by the coincidence of two of three pathological events: (1) intestinal ischemia; (2) colonization by pathogenic bacteria; and (3) excess protein substrate in the intestinal lumen.
Kosloske, supra, also reports that NEC is rare among infants fed only breast milk. In humans, breast milk plays a role in passive immunization of the neonatal intestine, and contains factors that promote the growth of Bifidobacterium in the intestinal flora. It is also reported that the beneficial contents of human milk may be adversely affected by freezing, pasteurization, or storage.
Thus, there is much debate about the etiology and treatment of NEC and there remains a need for compositions and methods that are better able
Benson John D.
Borror David A.
Carlson Susan E.
Diodato David V.
Dohnalek Margaret H.
Abbott Laboratories
Brainard Thomas D.
Spivack Phyllis G.
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