Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-07-29
2001-08-21
Saoud, Christine J. (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S399000, C530S412000
Reexamination Certificate
active
06277813
ABSTRACT:
The present invention relates to a novel growth factor present in colostrum, to a composition comprising said growth factor and the pharmaceutical uses thereof.
The present invention provides the novel polypeptide CDGF (colostrum derived growth factor).
Further, the present invention provides the use of CDGF in medical and veterinary applications. In particular, the present invention provides the use of CDGF to promote the growth and/or function of tissues as well as the use of CDGF to combat or alleviate disease states or abnormalities. Thus CDGF may have particular utility for wound healing applications (for example following accidents or surgery) and to combat or alleviate disease conditions where tissue regeneration is required (for example ulcers). CDGF may also be of utility in combating deleterious side effects of other drug regimes, in particular in decreasing the side effects of chemotherapy or radiotherapy treatment for cancer, especially in combating the influence of such treatments on the gastrointestinal tract. CDGF is believed to be of particular utility for tissue derived from the gastrointestinal tract, skeletal muscle, liver and glandular tissue (especially the mammary gland), but the invention is not limited to use in respect of these organs alone.
In more detail, CDGF may be helpful in treating post-operative patients to promote healthy tissue regeneration, and CDGF treatment following the surgical removal of tumours is believed to be particularly beneficial.
One of the effects of CDGF is to promote tight junctions between the cells lining the gastrointestinal tract. This is of importance for pre-term neonates, which will possess an immature and “leaky” intestine (ie the junctions between the cells of the intestine are not sufficiently tight). This in turn can affect the absorbance of nutrients. Likewise neonates which are atopic (and are thus prone to allergy) have also been shown to have immature “leaky” intestines. Administration of CDGF (either as a medicament or as a food supplement) may therefore be advantageous in promoting the maturation of the gastrointestinal tract of such neonates.
In a related manner, patients requiring total parenteral nutrition (tpn) may benefit from receiving CDGF, either in a separate formulation or as a component of the tpn composition.
With regard to the gastrointestinal tract, CDGF may:
a) Promote the regeneration of damaged tissue.
b) Promote intestinal and body function of pre-term neonates, nutritionally compromised neonates
c) Promote the barrier function of the gastrointestinal tact, thus enhancing disease resistance.
d) Combat intestinal colonisation by micro-organism (especially bacterial) pathogens.
In another aspect the present invention provides a composition comprising CDGF together with an inert carrier or excipient.
Desirably the composition may be formulated for therapeutic applications (including prophylactic therapeutic applications), and the carrier or excipient should-be chosen accordingly.
Alternatively the composition may be formulated as a food supplement or food substance. For example, the present invention includes baby food formulations comprising CDGF and also tpn formulations or invalid food formulations comprising CDGF.
In addition to CDGF the composition may comprise other ingredients. Mention may be made of inter alia, biologically active ingredients (for example antibiotics; other growth factors such as IGF, EGF, FGF or PDGF including combinations of cytokines with amino acids or polyamines (for example IGF/glutamine combinations); insulin; cytokines for example interleukins or any other agent having a biologically desirable effect), viscosity adjusting agents; osmosity adjusting agents, buffers, pH adjusting agents, flavourings, stabilisers, colourings, preservations and the like. Delayed release or controlled release formulations are also included.
The composition of the present invention may be formulated for administration by any suitable means. Particular mention may be made of oral, enteral, parenteral, sub-cutaneous and nasal routes of administrations. The composition may be prepared as a spray, solution, suspension, colloid, concentrate, powder, granules, tablets, pressed tablets, capsules (including coated and uncoated tablets and capsules), suppository and the like. Delayed release or controlled release formulations are also included.
Advantageously the composition will be sterile, and will be suitable for medical use.
The composition may be used as outlined above for CDGF, and such use forms a further aspect of the present invention.
In another aspect the present invention provides the use of CDGF or in the manufacture of a medicament for pharmaceutical use.
In a yet further aspect the present invention provides a method of treatment of the human or non-human (preferably mammalian) animal body, said method comprising administering a therapeutically effective amount of CDGF or a composition comprising CDGF to said body.
The method of treatment described above may be to combat invasion of the body (especially the gastrointestinal tract) by pathogens; to promote wound healing; to promote organ (for example intestinal) growth and development (especially in neonates or nutritionally or disease compromised adults). The method may also be of utility in promoting adaptation of the gastrointestinal tract to a change in diet.
Reference is made above to the polypeptide CDGF. This polypeptide (the term “polypeptide” as used herein refers to any peptide molecule, regardless of molecular size, shape or construction) is an active factor derived from colostrum. Porcine colostrum is mentioned as a suitable source of CDGF. CDGF is initially found to be bound to a large carrier molecule, giving an apparent molecular weight of over 200 kDa.
CDGF has been measured to have a molecular weight in the range of 60-80 kDa. CDGF is hydrophobic.
CDGF has been found to have the following physical characteristics:
1) Activity abolished by proteolytic enzymes (trypsin).
2) Essentially heat stable (over 70% activity retained) after heating to 100° C. for 10 minutes.
3) Stable in 2.4M formic acid.
4) Stable and soluble in 100% of 0.1% trifluoroacetic acid.
5) Activity is retained after treatment with 50 mM dithiothreitol.
6) Stable in 50% acetonitrile.
7) Stable and soluble in 50% ethanol.
The purification of CDGF from porcine colostrum is described in detail in the Examples. However, the process may be briefly summarised as follows:
a) separation of all components of colostrum having a molecular weight of over 200 kDa. (Components having a molecular weight below this cut-off are discarded);
b) treatment of the product of step (a) with dithiothreitol and boiled for 10 minutes; and
c) The mixture of step (b) is centrifuged to spin down any precipitated matter; CDGF is located in the supernatant.
CDGF may be identified as providing the following biological effects:
1) Stimulates proliferation of intestinal cells in in vitro cultures.
2) Promotes the differentiation of intestinal cells as measured by lactase activity and protein glycosylation.
3) Phosphorylation of membrane proteins of MVM vesicles in the phosphorylation assay described in the Examples.
4) Stimulation of the Ras pathway via GAP in MVM vesicles.
5) Stimulation of the genes c-myc and fos.
REFERENCES:
Database WPI, Section Ch, Week 9631, Derwent Publications Ltd., Class B04, AN 96-306444, XP002017833 & JP,A,08 133 943 (Kyodo Nyugyo KK), May 28, 1996.
Burrin et al., “Nutrient-Independent and Nutrient-Dependent Factors Stimulate Protein Synthesis in Colostrum-Fed Newborn Pigs”, Pediatric Research, vol. 37, No. 5, May 1995, p. 593-599.
Ratner & Prestia
Saoud Christine J.
The Rowett Research Institute
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