What is claimed is:
1. An isolated polynucleotide comprising the nucleotide sequence set forth in SEQ ID NO:1.
2. The isolated polynucleotide of claim 1 wherein the polynucleotide consists of a nucleotide sequence of the formula
(R1)m-SEQ ID NO:1-(R2)n
wherein R1 and R2 are independently any nucleic acid residue, and m and n are each integers between 1 and 1000.
3. The isolated polynucleotide of claim 2 wherein the polynucleotide consists of the nucleotide sequence set forth in SEQ ID NO:1.
4. An isolated polynucleotide that encodes a polypeptide comprising the amino acid sequence set forth in SEQ ID NO:2.
5. The isolated polynucleotide of claim 4 wherein the polynucleotide encodes the amino acid sequence set forth in SEQ ID NO:2.
6. An isolated polypeptide comprising the amino acid sequence set forth in SEQ ID NO:2.
7. The isolated polypeptide of claim 6 wherein the polypeptide consists of an amino acid sequence of the formula
(R1)m-SEQ ID NO:2-(R2)n
wherein, at the amino terminus, R1 and R2 are independently any amino acid residue, and m and n are each integers between 1 and 1000.
8. The isolated polypeptide of claim 6 consisting of the amino acid sequence set forth in SEQ ID NO:2.
9. An expression vector comprising the isolated polynucleotide of claim 4 when said expression vector is present in a compatible host cell.
10. An isolated host cell comprising the expression vector of claim 9.
11. A process for producing a polypeptide comprising the amino acid sequence set forth in SEQ ID NO:2 comprising culturing the host cell of claim 10 and recovering the polypeptide from the culture.
12. A membrane of the host cell of claim 10 expressing said polypeptide.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. An oral controlled release formulation which provides a rapid onset of therapeutic effect and a rapid drop in plasma concentration after a prolonged period of therapeutic effect, comprising a plurality of matrix particulates comprising:
a first portion of an effective dose of methylphenidate or a pharmaceutically acceptable salt thereof incorporated in a controlled release matrix,
a hydrophobic material comprising an acrylic polymer applied over the controlled release matrix in an amount sufficient to retard the release of the first portion of methylphenidate or a pharmaceutically acceptable salt thereof from the controlled release matrix;
an enteric coating applied over the hydrophobic material in an amount sufficient to substantially delay the release of said drug from said substrate until after said formulation passes through the stomach, wherein said enteric coating is derived from an aqueous dispersion comprising an acrylicmethacrylic copolymer, a plasticizer and a glidant; and
a topcoat comprising a second portion of the methylphenidate or a pharmaceutically acceptable salt thereof in immediate release form; wherein the formulation provides a time to mean maximum plasma concentration of methylphenidate at about 0.5 to about 4 hours after oral administration.
2. The formulation of claim 1, wherein a unit dose comprises the matrix particulates contained within a gelatin capsule, and the second portion of the methyiphenidate or pharmaceutically acceptable salt thereof is contained within the gelatin capsule in a form selected from the group consisting of an immediate release powder, an immediate release granulate, immediate release matrix spheroids, immediate release beads, and as a coating applied onto the surface of the enteric coated matrix particulates.
3. The formulation of claim 1, wherein the matrix particulates are compressed into a tablet.
4. The formulation of claim 1, wherein the matrix particulates are subjected to oven curing at a temperature above the glass transition temperature of the acrylic polymer at a temperature from about 40 to about 500\xb0C for a time period of at least about 12 hours prior to the application of the enteric coating.
5. The formulation of claim 1, which provides a peak plasma concentration of methylphenidate which is from about 1.0 to about 2.0 times the plasma concentration of methylphenidate provided by the formulation at about 9 hours after oral administration.
6. The formulation of claim 5, wherein the duration of effect provided by methylphenidate falls below effective plasma concentrations at about 8 to about 12 hours after oral administration.
7. The formulation of claim 6, wherein the formulation provides a time to mean maximum plasma concentration at about 0.5 to about 2 hours after oral administration.
8. The formulation of claim 5, wherein the peak plasma concentration is from about 1.0 to about 1.7 times the plasma concentration of the methylphenidate provided by the formulation at about 9 hours after oral administration.
9. The formulation of claim 5, wherein the duration of effect provided by methylphenidate falls below effective plasma concentrations at about 8 to about 10 hours after oral administration.
10. The formulation of claim 9, which provides a \u201csquare wave\u201d plasma profile.
11. The formulation of claim 9, which provides an in-vitro dissolution as follows:
Time
% Methylphenidate
(hours)
Dissolved
\u20020.25
\u20020-45%
\u20021
\u20025-50%
\u20024
40-90%
\u20028
NLT 60%
12
NLT 80%.