Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
2001-05-03
2004-02-24
Brumback, Brenda (Department: 1654)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C530S327000, C530S328000, C530S332000, C514S014800, C514S015800, C514S016700
Reexamination Certificate
active
06696274
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to a composition comprising a peptide or analog or derivative thereof (Ligand) that is capable of enhancing oral and CNS bioavailability of therapeutics. More particularly, the present invention involves compositions comprised of a Ligand, or a complex of a Ligand with a carrier, which is associated with a biological agent.
BACKGROUND OF THE INVENTION
Optimized bioavailability of drugs administrated by oral route is one of the most important aims of the pharmaceutical industry during the development phase of a new product. Bioavailability represents both the quantity of a biological agent, i.e. the active component, absorbed from a pharmaceutical composition that is absorbed into blood and circulated, and the rate of this absorption. This implies that the molecule crosses one or several biological membranes before reaching the blood circulation. It has been generally considered that the physico-chemical properties of an orally administered drug determine its bioavailability. Among these parameters are the molecular weight (very low permeability is known for therapeutics with molecular weight more than 600 D), the pKa, and the lipophilicity as characterized by the octanol/water partition coefficient (Log D). The quantity of drug reaching the general circulation depends on the drug quantity absorbed by the intestinal epithelium, and drug solubility and stability in the gastrointestinal tract. Many classes of drugs present a large inter-individual variability in their absorption and/or a low bioavailability. Cytotoxic drugs used in anticancer therapy are a good example of drugs that are often poorly absorbed. Therapeutic peptides and proteins have also very low bioavailability by the oral route because they are easily metabolized in the stomach and intestine. In addition to problems related to degradation, the molecular weights of such peptides and proteins are typically too high to allow for significant transport across the gut wall into the circulatory system.
Since the advent of biotechnology, many protein therapeutics have been identified as having significant therapeutic benefits for many potentially serious diseases. Such diseases include cancer, heart disease, diseases of the central nervous system, diseases of the immune system, diseases of the blood and circulatory system, and many hormonally based diseases. Many of these medical disorders are chronic and require continuous administration of the required therapeutic.
A broad utilization of protein therapeutics, and many other hard to deliver therapeutics, depends on the ability of easily administering them to patients in a controllable and acceptable manner. The conventional route of therapy involving protein or peptide drugs is via parenteral administration (i.e., by injection), principally due to the lack of absorption of such drugs through the gastrointestinal tract. However, injections are painful and sometimes difficult to administer relative to other administration methods. Patient compliance is also an important consideration, since some of these drugs may require frequent administration to juvenile or geriatric patients. Clearly, oral administration is the most desirable method for administering such compounds to patients, who must take them for extended periods of time.
Although oral vaccination is more convenient, vaccines are generally given through injection. This is particularly true with killed or peptidic vaccines, because of their low absorption into the gastrointestinal tract. A problem with systemic immunization however, is that it may not effectively induce mucosal immune responses, for example, production of IgA, that are important as the first defense barrier to invaded microorganisms. For this reason, it would be beneficial to provide oral vaccination, if the problems of low intestinal absorption are resolved.
Recent efforts to deliver polypeptides and vaccines orally have focused on the use of absorption enhancers. This has led to the discovery that a suspension of sodium salicylate in an excess of oil can enhance the absorption of human growth hormone from the GI tract (EP publication 177,342; Moore et al., Internat. J. Phama. 34: 35 (1986)). While absorption is improved by this combination, the highest achievable bioavailability of the protein is only up to about 10-20% (with reference to intravenous administration), which is still quite low. As a result, larger amounts of proteins must be administered orally in order to provide the required therapeutic level of protein in the plasma. This is a particular problem with proteins and polypeptides that, even with the advent of biotechnology, are still of relatively limited availability, are complex chemical entities, and thus are very expensive. While the formulations discussed above have been found to improve absorption of proteins, polypeptides, and peptides in the colon somewhat, they also possess the inherent limitations and disadvantages explained above.
Accordingly, what is need is a novel and useful product that increases the absorption into the circulatory system from the gastrointestinal tract of a biological agent that is administered orally. What is also needed is a novel and useful product that increases absorption of a therapeutic agent across the Blood Brain Barrier (BBB), and thus increases the CNS bioavailability of a therapeutic agent.
The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.
SUMMARY OF THE INVENTION
The present invention provides a polypeptide comprising at least one peptide or derivative thereof, wherein the polypeptide or derivative thereof is capable of crossing the small intestine and blood brain barrier. Such a polypeptide is herein referred to as Ligand.
In one embodiment, the present invention provides a peptide or derivative thereof that capable of is crossing the small intestine and blood brain barrier.
The polypeptide of the present invention comprising at least one peptide or derivative thereof, wherein the polypeptide or derivative thereof is capable of delivering biological agents across the small intestine and blood brain barrier.
A preferred peptide of the present invention provides the amino acid sequence of Arg-Val-Leu-Asp-Gly-Asp-Arg-Thr-Arg-Trp-Gly (SEQ. ID. NO.:4) wherein the peptide is capable of crossing the small intestine and blood brain barrier and delivering biological agents across the small intestine and blood brain barrier.
The present invention further provides a polypeptide, wherein the polypeptide or derivative thereof comprise the amino acid sequence of SEQ. ID. Nos.: 1, 2, 3, 4, 5, 6, or 7.
A preferred peptide, variant or derivative of peptide of the present invention has the sequence Arg-Val-X-Asp-X-Asp-X-Thr (SEQ. ID. NO.:7) (also abbreviated in single letter amino acid code as R V X D X D X T), where X is any amino acid).
Another embodiment of the present invention provides at least one peptide compound having the motif SEQ. ID. NO.:6:
Y
1
-Y
2
-X-Y
3
-X-Y
4
-X-Y
5
, where
Y
1
is positively charged amino acid such as Arg or Lys
Y
2
is Val, Leu, Ile or Met
Y
3
is negatively charged amino acid such as Glu or Asp
Y
4
is negatively charged amino acid such as of Glu or Asp
Y
5
is Thr or Ser
X is any amino acid.
The polypeptide of the present invention further provides an extension at the carboxyl termini of polypeptide or derivative thereof wherein the carboxyl termini amino acid of the polypeptide or derivative thereof is bound to the C-terminal carboxyl group of the peptide. One embodiment of the present invention provides a pharmaceutical composition comprising the amino acid sequence of SEQ. ID. Nos.: 2, 3, or 5 wherein the carboxyl termini of alanine of said SEQ. ID. Nos.: 2, 3, or 5 is bound to carboxytetramethylrodamine.
The present invention also provides analogs of the polypeptide which can comprise in its molecular structure residues being derivatives of compounds other than amino acids, referenced herein as “pept
Alakhov Valery
Li Shengmin
Pietrzynski Grzegorz
Tchistiakova Lioudmila
Brumback Brenda
Chism Billy D
Gibbons Del Deo Dolan Griffinger & Vecchione
Supratek Pharma Inc.
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