1. A method of strengthening a skin barrier comprising: applying a composition to the skin of a mammal, wherein the composition comprises: a nicotinic acid adenine dinucleotide phosphate (NAADP) expressed as the following Chemical Formula 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, thereof, as an active ingredient,
where,
R1 and R2 are each independently H, C1-4 alkyl, unsubstituted or substituted with halogen, or CH2\u2014CO\u2014CH3;
W is selected from the group consisting of NH2, OH, and SH;
X is selected from the group consisting of OH, SH, NH2, and halogen; and,
Y is selected from the group consisting of OH, H, NH2, and halogen.
2. The method of claim 1, wherein the pharmaceutical composition is used for treating skin diseases and disorders including psoriasis, atopic dermatitis, ichthyosis, primary contact dermatitis, allergic contact dermatitis, allergic dermatitis, xeroderma, eczema, skin atrophy due to steroid side effects, skin wounds, scars, wrinkles, skin aging, generation of age spots, or weakening of skin resilience.
3. The method of claim 1, wherein the pharmaceutical composition is formulated as a skin external preparation selected from the group consisting of a solution, a suspension, an emulsion, ointment, gel, paste, cream, lotion, powder, spray, a pack and a skin adhesive patch, a dressing, a hydrous adhesive patch, or an anhydrous adhesive patch.
4. The method of claim 3, wherein, with respect to a skin external preparation, a dose of the active ingredient is in a range of 1 nM to 100 \u03bcM per a skin surface area (cm2) for a day.
5. The method of claim 1, wherein applying the composition comprises applying a functional cosmetic composition.
6. A method of promoting differentiation of keratinocytes of mammals, the method comprising contacting keratinocytes separated from skin of mammals and culturing said separated keratinocytes with a composition comprising a nicotinic acid adenine dinucleotide phosphate (NAADP) expressed as the following Chemical Formula 1, or a salt, or a solvate thereof, as an active ingredient,
where,
R1 and R2 are each independently H, C1-4 alkyl, unsubstituted or substituted with halogen, or CH2\u2014CO\u2014CH3;
W is selected from the group consisting of NH2, OH, and SH;
X is selected from the group consisting of OH, SH, NH2, and halogen; and,
Y is selected from the group consisting of OH, H, NH2, and halogen.
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. A process for synthesizing valsartan substantially free of its isoleucine analogue comprising the steps of:
a) obtaining one or more samples of at least a single valine or valine derivative batch;
b) measuring the level of isoleucine or corresponding isoleucine derivative in each of the samples of step (a);
c) selecting the batch of valine or its derivative that comprises a level of isoleucine or isoleucine derivative of less than about 0.1% as area percentage GC based on the measurement or measurements conducted in step (b); and
d) using the batch selected in step (c) to synthesize said valsartan.
2. The process of claim 1, wherein the valsartan contains less than about 0.1% as area percentage HPLC its corresponding isoleucine derivative.
3. The process of claim 2, wherein the level is 0.07%.
4. The process of claim 1, wherein the level of the isoleucine or the corresponding isoleucine derivative in the batch of valine or its derivative of step (c) is less than about 0.07% as area percentage GC.
5. A process for preparing valsartan comprising synthesizing valsartan from an initial sample of valine or a valine derivative, wherein the process analyzes the level of isoleucine or corresponding isoleucine derivative present in the initial sample at least at a single stage during the synthetic process to control amount of an impurity having the following structure:
being present in valsartan.
6. The process of claim 5 wherein the desirable level of the isoleucine analogue is NMT 0.1% as area percentage HPLC.
7. The process of claim 1, 2, 3, 4, 5 or 6, wherein the analysis is carried out of the valine derivative in regard to its corresponding isoleucine derivative.
8. The process of claim 7, wherein the derivative that is analyzed is a methyl ester.
9. A process for preparing valsartan comprising the steps of:
a) analyzing a C1 to C4 alkyl ester of L-valine for presence of its isoleucine analogue as an impurity;
b) selecting a sample that has NMT about 0.1% as area percentage GC of the isoleucine analogue of L-valine as determined by HPLC;
c) reacting compound G2:
with the L-valine ester in a first organic solvent to obtain a compound G3:
reacting compound G3 with an acylating agent in a second organic solvent to obtain a compound G4;
and
e) hydrolyzing compound G4 to obtain valsartan.
wherein A is a C1 to C4 alkyl ester, X is a trityl group and L is a leaving group.
10. The process of claim 9, wherein the first and second organic solvents are independently selected from the group consisting of acetonitrile, toluene, acetone, ethyl acetate, dimethyl acetamide, DMF, hexane and mixtures thereof.
11. The process of claim 10, wherein step (c) is carried out in acetonitrile.
12. The process of claim 9, wherein the valsartan contains less than 0.1% of its corresponding isoleucine derivative as area percentage HPLC.
13. The valsartan prepared by the process of any of claims 1, 2, 3, 4, 5, 6, 9, 10, 11, or 12.
14. A pharmaceutical composition of valsartan comprising valsartan substantially free of its isoleucine analogue and a pharmaceutically acceptable excipient.
15. A method of lowering systematic blood pressure in a human in need thereof comprising the step of administering the pharmaceutical composition of claim 14 to the human.