Tamsulosin is (R)-5-(2-{[2-(2-ethoxyphenoxy)ethyl]amino}propyl)-2-methoxybenzene-1-sulfonamide of the following structural formula. This compound was first disclosed, as well as pharmaceutically acceptable salts thereof, in patent literature 1.

Tamsulosin or its salts are known to have an activity of blocking adrenergic receptor α1A. In particular, tamsulosin hydrochloride has an activity of blocking α1 receptors in the urethra and prostate, and is widely used as an agent for treating dysuria associated with benign prostatic hyperplasia by reducing prostatic pressure in urethral pressure profile. It has been clinically confirmed that tamsulosin hydrochloride is effective in treating lower urinary tract symptoms, and thus, tamsulosin hydrochloride is an extremely useful drug in clinical use. Tamsulosin is placed on the market as Harnal (registered trademark) in Japan, Flomax (registered trademark) in the United States, and Omnic (registered trademark) in Europe.
Solifenacin is represented by the following structural formula, and its chemical name is (R)-quinuclidin-3-yl (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate.

It has been reported that solifenacin or its salts have an excellent selective antagonistic activity against muscarinic M3 receptors, and are useful as an agent for preventing or treating urinary diseases such as urinary incontinence and pollakiuria in neurogenic pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm, and chronic cystitis; respiratory diseases such as chronic obstructive pulmonary diseases, chronic bronchitis, asthma, and rhinitis; and digestive diseases such as irritable bowel syndrome, spastic colitis, and diverticulitis (see patent literature 2).
In particular, solifenacin has high selectivity for M3 receptors located in the smooth muscles, gland tissues, or the like, in comparison with M2 receptors located in the heart or the like, and is useful as an M3 receptor antagonist with less side effects on the heart or the like, in particular, as an agent for preventing or treating urinary incontinence and pollakiuria, chronic obstructive pulmonary diseases, chronic bronchitis, asthma, rhinitis, and the like. Solifenacin is placed on the market, as an agent for treating urinary urgency, urinary frequency, and urge incontinence in overactive bladder, as Vesicare (registered trademark) in Japan, VESIcare (registered trademark) in the United States, and Vesicare (registered trademark) in Europe.
A modified release formulation containing tamsulosin or a pharmaceutically acceptable salt is known (for example, patent literatures 3 and 4), and is placed on the market as Omnic OCAS (registered trademark).
This provides a modified release formulation with a blood drug concentration profile showing a lower peak/trough ratio than that of a conventional modified release formulation. The modified release formulation not only reduces the occurrence of side effects such as orthostatic anemia, but also is expected to increase the dose or sustain the efficacy for a long period. Further, food effects on blood drug concentrations can be avoided, and a high safety profile is expected in view of drug dosing compliance (patent literature 5).
To treat lower urinary tract symptoms associated with benign prostatic hyperplasia, a pharmaceutical composition containing tamsulosin or a pharmaceutically acceptable salt thereof and solifenacin or a pharmaceutically acceptable salt thereof, more specifically, a pharmaceutical composition for treating lower urinary tract symptoms associated with benign prostatic hyperplasia, and an invention relates to a combination use of both drugs, are disclosed (patent literature 6).
Tamsulosin or a pharmaceutically acceptable salt thereof is effective in treating voiding symptoms and, by contrast, solifenacin or a pharmaceutically acceptable salt thereof is effected in treating storage symptoms, and thus, both compounds exhibit contradictory effects. However, the combination use of both drugs unexpectedly resulted in the further amelioration of storage symptoms without the decrease in amelioration of voiding symptoms, in comparison with a single administration of each drug alone.
Because it was confirmed that the combination therapy using tamsulosin or a pharmaceutically acceptable salt thereof and solifenacin or a pharmaceutically acceptable salt thereof was clinically effective in treating lower urinary tract symptoms associated with benign prostatic hyperplasia, it is desired to provide the medical field with a combined formulation (i.e., a single formulation) containing both drugs to improve drug dosing compliance. As an embodiment of the combined formulation for efficiently exhibiting the effects obtainable by the combination use, while maintaining the decreased occurrence of side effects and the sustainment of efficacies, a combined formulation of a modified release formulation containing tamsulosin with an ordinary formulation (an immediate release formulation) containing solifenacin may be proposed. However, because the drug dissolution rates in both formulations are different from each other, even when a single formulation (i.e., the combined formulation) is prepared from both formulations, it is desired that the drug releasing rate in each formulation contained in the single formulation is not much affected.
USPTO Backgrounds
USPTO Backgrounds