Topical doxycycline hydrogel with improved long-term stability

A method of making a composition for topical applications, comprising:

• doxycycline with carboxy-methyl-cellulose, glycerol, citric acid, and at least one pH stabilizer, wherein the doxycycline is added in an autoclaved CMC hydrogel after cooling to a temperature of 50 to 70 degrees Celsius;
• and
• a suspension or dispersion of particles of doxycycline chelated with calcium, the particles having an average diameter less than or equal to about 100 microns,
• wherein the composition is autoclaved above 100 degrees Celsius before the particles are precipitated at a temperature of 50 to 70 degrees Celsius,
• wherein the doxycycline chelated with calcium is present in an amount ranging from greater than about 0.1 weight % to about 3 weight %,
• wherein the composition includes less than 0.5 weight % 4-epidoxycycline when it has a yellow or yellow-brown color, and
• wherein the composition includes more than 0.5 weight % 4-epidoxycline when it has a brown color,
• wherein the composition is stable for 6 to 20 months under refrigeration, and
• wherein the formation of 4-epidoxycycline is less than 0.5 weight % per year under refrigeration.