Dorzolamide is a carbonic anhydrase inhibitor, and is one of the active ingredients in a topical drug for treating glaucoma (developed by Merck) called COSOPT®. The solubility of dorzolamide is 40 mg/mL at pH 4.0-5.5. It is a white to off-white, crystalline powder, which is soluble in water and slightly soluble in methanol and ethanol.
However, the COSOPT® formulation, which contains dorzolamide as the main active ingredient, is prepared at pH 5.65, due to the limited aqueous solubility of dorzolamide at physiological pH. Consequently, COSOPT® can lead to local irritation, due to the low pH. Dorzolamide has two pKa values of 6.35 and 8.5, which correspond to the protonized secondary amine group and the sulfonamide group, respectively. Dorzolamide is mainly in its hydrophilic cationic form at pH below 6.4, and in its hydrophilic anionic form above pH 8.5.
Thus, dorzolamide has a relatively low aqueous solubility in solutions with pH between 6.4 and 8.5, mainly because of dorzolamide's non-ionic behavior in that pH range.
AZOPT® (brinzolamide ophthalmic suspension) 1% is a sterile, aqueous suspension of brinzolamide, which has been formulated to be readily suspended and slow settling, following shaking. It has a pH of approximately 7.5 and an osmolality of 300 mOsm/kg. It is instilled for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Brinzolamide's pKa values are 5.9 (amine) and 8.4 (primary sulfonamide), allowing it to act as an acid or a base (ampholyte) depending upon the pH. It is mainly in its hydrophilic cationic form at pH below 5.9 and hydrophilic anionic form above pH 8.4. It is clear that brinzolamide is significantly less protonated (<10%) at physiological pH. Thus, brinzolamide has relatively low aqueous solubility in solutions with pH between 5.9 and 8.4, mainly because of brinzolamide is nonionic (lipophilic) behavior in that pH range.
Dendritic polymers are tree-like polymers that can be classified into two main types based on their branching architecture as “perfectly branched” (dendrimers) and “imperfectly branched” (hyperbranched polymers or HP). Hyperbranched polymers are molecular constructions having a branched structure, generally around a core. Unlike dendrimers, the structure of hyperbranched polymers generally lacks symmetry, as the base units or monomers used to construct the hyperbranched polymer can be of diverse nature and their distribution is non-uniform. The branches of the polymer can be of different natures and lengths. The number of base units, or monomers, may be different depending on the different branching. While at the same time being asymmetrical, hyperbranched polymers can have: an extremely branched structure, around a core; successive generations or layers of branching; a layer of end chains. Hyperbranched polymers are generally derived from the polycondensation of one or more monomers ABx, A and B being reactive groups capable of reacting together, x being an integer greater than or equal to 2. However, other preparation processes are also possible. Hyperbranched polymers are characterized by their degree of polymerization DP=1−b, b being the percentage of non-terminal functionalities in B which have not reacted with a group A. Since the condensation is not systematic, the degree of polymerization is less than 100%. An end group T can be reacted with the hyperbranched polymer to obtain a particular functionality on the ends of chains. See U.S. Pat. Nos. 6,432,423, 7,097,856, and U.S. Patent Publication 2006/0204472, the contents of which are incorporated herein by reference.
In contrast to the “structurally perfect” dendrimers prepared by multi-step synthesis, somewhat less perfect hyperbranched polymers can be synthesized in one-step reactions. Thus, unlike dendrimers, hyperbranched polymers are rapidly prepared with no purification steps needed for their preparation. Consequently, hyperbranched polymers are significantly less expensive than perfect dendrimers. Thus it makes HPs amenable for large-scale in vivo trials and bringing highly branched polymers as candidates for drug delivery of even common drugs as ibuprofen (Kannan, R. M. et al., Biomedical Applications of Nanotechnology, 2007, John Wiley & Sons Inc., p. 105).
USPTO Backgrounds
USPTO Backgrounds