KR20050018661A - Pharmaceutical combination for the treatment of benign prostatic hyperplasia or for the long-term prevention of acute urinary retention - Google Patents

Abstract

The present invention relates to novel pharmaceutical combinations for the treatment of benign prostatic hyperplasia (BPH) or for the long term prevention of acute urinary tract (AUR).

Description

Pharmaceutical combination for the treatment of benign prostatic hyperplasia or for the long-term prevention of acute urinary retention

The present invention relates to pharmaceutical formulations for the treatment of benign prostatic hyperplasia or for the long term prevention of acute urinary retention.

BPH, a benign, non-cancerous enlargement of the prostate gland, is generally a well-known disease for men who need medical attention after age 50. About 50% of all men over 50 and 95% of all men over 70 have this disease. BPH is a systemic progressive pathology that, in severe cases, may endanger kidney function and may require surgical procedures. The number of untreated patients is over 37 million worldwide. Reduced flow rate and urination (obstruction) symptoms of BPH are generally caused by two major factors: the enlarged prostate (static factor) and the tone (dynamic factor) of the stroma and smooth muscles of the urethra Is considered. Accumulation (irritation) symptoms are associated with bladder dysfunction following exhaust obstruction. An increase and tension in the prostate will compress or prolong the urethra, causing symptoms of urethral blockage and possibly causing urinary tract.

The prostate gland consists of an epithelial gland burying into the fibromuscular epilepsy. Hypertrophy growth of the prostate begins at about 30 years in the periphery of the gland, the so-called transition zone. Apart from the effects of aging, androgen hormones give significant stimulation to growth in pubertal regulation of the gland volume. In normal prostate, the enzyme 5α reductase in epithelial cells converts the androgen hormone testosterone (T) to dihydrotestosterone (DHT). DHT, an active androgen prostate metabolite, binds to cytoplasmic receptors and is transported to the cell nucleus, where it initiates the synthesis and cellular replication of RNA and proteins. It is estimated that BPH occurs in response to the effects of DHT on aging prostate and changes in epilepsy and epithelial cells. See Steers, Zorn, Dis . Mon. , 41 (7): 437-497 (1995).

Aging-dependent changes in serum concentrations throughout the hormone control pathways (LH, FSH, SHGB, T and DHT) and the serum concentrations of other hormones (oestrogen, prolactin, testosterone derivatives) that may affect these regulatory pathways Aging-dependent changes were considered as possible causes. However, there was no correlation between aging-dependent hormone changes in serum and hormone levels in the prostate. Thus, it is clear that the prostate itself will be involved in the regulation of the hormonal milieu.

Possible points of attack for regulating the hormonal environment in the prostate are 5α-reductase (ie androgen metabolism), hormone receptor expression in epithelium and epilepsy, oestrogens and other hormones, especially its type 2 isoforms. In addition, numerous peptide growth factors exhibit paracrine and autocrine effects on local metabolism within the various compartments of the gland, whereby cell dynamic equilibrium can be shifted between proliferation and scheduled cell death. .

 Clinical symptoms of BPH include blockage (urination, obstruction) symptoms that are directly caused by prostate urethra due to prostatic hyperplasia and cervical compression of the bladder (e.g., urinary, weak or discontinued urine, postureteria, acute urinary AUR), arrest of urinary flow), and stimulated accumulation of the lower urinary tract (stimulation) symptoms (eg, urinary frequency, nocturia, difficulty in urination, urinary incontinence, urinary incontinence, uresiesthesis). Untreated BPH can cause serious complications of the urinary tract and kidneys, such as acute urinary tract and hydronephrosis (urecemia).

Tamsulosin hydrochloride is an α-receptor blocker, a selective α ₁ -adrenergic receptor antagonist, used as a single substance to treat functional symptoms of prostatic hyperplasia (BPH) or lower urinary tract symptoms (LUTS) associated with prostatic hyperplasia (BPH) do. Tamsulosin mediates the dynamic elements of LUTS to improve both accumulation and urination symptoms in BPH patients. The onset of action is rapid and persists in prolonged treatment regardless of the size of the prostate. The need for BPH-surgery and catheterization (mainly due to AUR) is significantly slowed down.

The synthesis of tamsulosin and acid addition salts thereof is described for the first time in European Patent No. EP 34432, incorporated herein by reference.

Suitable sustained release formulations are described, for example, in US Pat. No. 4,772,475, also referenced herein.

5α-reductage inhibitors, and especially inhibitors of type 2 isoforms of the enzymes, are used to treat BPH. 5α-reductase inhibitors can reduce the benign hypertrophic prostate (a static component of BPH) and consequently reduce to some extent accumulation and urination symptoms. Onset of action is delayed, but in the long term, the risk of acute urinary tract and the need for BPH surgery may be reduced.

Examples of such inhibitors are the compounds described in US Pat. No. 4,760,071, EP 285382, EP 285383 and WO 95/7927, and more specifically finasterides (for example EP 155096 and US Pat. No. 4,760,071). And dutasterides (for example described in WO 95/7927). In addition, compounds with 5α-reductase type 2 inhibitor activity can be determined using the assays described in Example 3 of WO 95/10284.

These compounds as well as their pharmaceutically acceptable salts and their optically active isoforms are all incorporated herein by reference.

Summary of the Invention

The present invention relates to pharmaceutical combinations containing tamsulosin and testosterone 5α-reductase inhibitors. The combination according to the invention is suitable for the treatment of benign prostatic hyperplasia.

Surprisingly, the combinations according to the invention of tamsulosin or acid addition salts thereof, in particular tamsulosin hydrochloride and 5α-reductase inhibitors, in particular inhibitors of type 2 isoforms of the enzymes, are suitable for the treatment of benign prostatic hyperplasia, It will provide additional advantages over each monotherapy.

In a preferred embodiment according to the invention, the 5α-reductase type 2 inhibitors are finasterides and dutasterides.

In another preferred aspect according to the invention, the combination is a combination of tamsulosin and finasteride or a combination of tamsulosin and dutasteride, which combination is particularly suitable for the long term treatment of benign prostatic hyperplasia.

In another preferred embodiment, the combination according to the invention contains two active substances, 0.1 to 0.8 mg of tamsulosin hydrochloride and 0.3 to 8 mg of 5α-reductase type 2 inhibitor in one formulation. The active substance can be administered orally.

In another preferred embodiment, the combination according to the invention is a solid pharmaceutical formulation containing 0.1 to 0.8 mg of tamsulosin hydrochloride and 0.3 to 8 mg of a 5α-reductase type 2 inhibitor. The active substance can be administered orally.

In another preferred embodiment, the combination according to the invention contains two active substances, 0.2-0.6 mg tamsulosin hydrochloride and 0.3-8 mg 5α-reductase type 2 inhibitor, in one formulation. The active substance can be administered orally.

In another preferred embodiment, the combination according to the invention is a pharmaceutical combination containing 0.2 to 0.6 mg of tamsulosin hydrochloride and 0.3 to 0.5 mg of a 5α-reductase type 2 inhibitor. The active substance may be administered orally and may be in solid dosage form.

In another preferred embodiment, the combination according to the invention is a pharmaceutical combination containing 0.2 to 0.6 mg of tamsulosin hydrochloride and 0.3 to 8 mg of a 5α-reductase type 2 inhibitor. The active substance may be administered orally and may be in solid dosage form.

Examples of the following formulations are intended to illustrate the present invention.

A formulation containing 0.1 to 0.8 mg of tamsulosin hydrochloride and 1 to 8 mg of finasteride.

A formulation containing 0.1 to 0.6 mg of tamsulosin hydrochloride and 1 to 8 mg of finasteride.

A pharmaceutical combination containing 0.2 to 0.4 mg of tamsulosin hydrochloride and 1 to 8 mg of finasteride.

A formulation containing 0.1 to 0.8 mg of tamsulosin hydrochloride and 0.3 to 0.5 mg of finasteride.

A formulation containing 0.1 to 0.6 mg of tamsulosin hydrochloride and 0.3 to 0.5 mg of finasteride.

Pharmaceutical formulation containing 0.2 to 0.4 mg of tamsulosin hydrochloride and 0.3 to 0.5 mg of finasteride.

A formulation containing 0.1 to 0.8 mg of tamsulosin hydrochloride and 1 to 8 mg of dutasteride.

A formulation containing 0.1 to 0.6 mg of tamsulosin hydrochloride and 1 to 8 mg of dutasteride.

Pharmaceutical formulation containing 0.2 to 0.4 mg of tamsulosin hydrochloride and 1 to 8 mg of dutasteride.

A formulation containing 0.1 to 0.8 mg of tamsulosin hydrochloride and 0.3 to 0.5 mg of dutasteride.

A formulation containing 0.1 to 0.6 mg of tamsulosin hydrochloride and 0.3 to 0.5 mg of dutasteride.

A pharmaceutical combination containing 0.2 to 0.4 mg of tamsulosin hydrochloride and 0.3 to 0.5 mg of dutasteride.

These illustrated formulations may be in the form of solid pharmaceutical dosage forms and may be administered orally.

Suitable conventional formulations are, for example, corn starch, lactose, which are incorporated in conventional herbal formulations such as simple tablets or epidermal tablets, capsules, powders, suspensions or suppositories together with conventional inert carriers and / or diluents, for example. Glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / alcohol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl Cellulose or fatty substances (eg hard fat) or suitable mixtures thereof.

The active substances can be administered orally in a wide variety of different dosage forms: for example, they are tablets, capsules, pastilles, lozenges, hard sweets together with various pharmaceutically acceptable inert carriers. , Powders, aqueous suspensions, elixirs, syrups and the like. Carriers of this kind include, for example, solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. In addition, oral formulations of this kind may be appropriately flavored and / or flavored with the various agents conventionally used for this purpose. Generally, the active substance is present in this kind of oral dosage form in an amount sufficient to produce the desired dosage unit, at a concentration ranging from about 0.5% to about 90% by weight based on the total composition. Other dosage forms of the active substance include formulations for controlled release and designs well known to those skilled in the art.

Preferably, the two active substances are in delayed-release formulations.

Within the scope of the present invention, two active agents may be present in the same formulation or in two separate formulations. In the latter case, formulations containing the active substance can be administered simultaneously or sequentially.

According to the invention, the expression 'long term treatment' refers to the medical application of a combination of two active substances in one or more formulations for at least 3 months.

The combinations according to the invention are particularly suitable for treating patients with an enlarged prostate and suffering from lower urinary tract symptoms (LUTS) and / or face a limited increased risk of disease progression, such as long-term prevention of acute urinary tract (AUR). It is believed to be manifested.

Claims (8)

A pharmaceutical formulation containing a combination of tamsulosin or an acid addition salt thereof with a 5α-reductase inhibitor. The pharmaceutical combination according to claim 1, wherein the 5α-reductase inhibitor is an inhibitor of type 2 isoform of 5α-reductase enzyme. The pharmaceutical combination according to claim 1 or 2, which contains tamsulosin hydrochloride. The pharmaceutical combination according to any one of claims 1 to 3, wherein the 5α-reductase inhibitor is finasteride. The pharmaceutical combination according to any one of claims 1 to 3, wherein the 5α-reductase inhibitor is dutasteride. The pharmaceutical combination according to any one of claims 1 to 5 for the treatment of benign prostatic hyperplasia. The pharmaceutical combination according to any one of claims 1 to 6 for long term treatment of benign prostatic hyperplasia. The pharmaceutical combination according to any one of claims 1 to 5 for long term prevention of acute urinary tract.