WO2023061438A1 - Pharmaceutical composition and use thereof - Google Patents

Abstract

A pharmaceutical composition and the use thereof. The composition contains silodosin and Finasteride as active components. Use of the composition in the preparation of a drug for inhibiting the contraction of prostate smooth muscle or inhibiting the proliferation of prostate, and use of the composition in the preparation of a drug for improving frequent urination and urinary incontinence. The composition can be used for treating or preventing benign prostatic hyperplasia (BPH) and the symptoms and signs caused by benign prostatic hyperplasia.

Description

A kind of pharmaceutical composition and its application technical field

The invention relates to the field of medicines, in particular to a pharmaceutical composition containing silodosin and finasteride and its application. The composition can be used in the preparation of medicines for treating or preventing benign prostatic hyperplasia (BPH) and the symptoms and signs caused by it.

Background technique

Benign prostatic hyperplasia (BPH) is a condition with symptoms of an enlarged prostate. The process of benign prostatic hyperplasia can cause pressure on the urethra and increase the tone of the smooth muscle of the prostate. Therefore, the occurrence of BPH usually causes symptoms of lower urinary tract symptoms (LUTS) and bladder outlet obstruction (BOO). The clinical symptoms of BPH include frequent urination, urgency, urinary incontinence, increased nocturia, hesitancy to urinate, dysuria, intermittent urination, incomplete urination, post-urination dribbling, etc. In severe cases, symptoms such as urinary stones, hematuria, and renal failure may even occur. Not only the number of BPH patients increases dramatically with increasing age, but also the number of critically ill patients, highly affecting the quality of life.

At present, there are many researches on the therapeutic drugs of BPH. Existing reports suggest that the pathogenesis of BPH needs to consider static factors and dynamic factors. The former refers to the growth of prostate tissue, and the latter refers to the contraction of smooth muscle. BPH and the signs and symptoms it causes can be treated by inhibiting the growth of the prostate and improving the contraction of the smooth muscle of the prostate.

α1-adrenergic receptors are present in large quantities in bladder, urethral smooth muscle, and prostate tissue. α1-adrenergic receptors can stimulate smooth muscle contraction, thereby increasing urethral resistance. α1-adrenergic receptor antagonists can improve urethral resistance and reduce the occurrence of BOO by relaxing the smooth muscles in the prostate and bladder neck, and are effective drugs for the treatment of BPH. Silodosin (Silodosin) is a highly selective α1A-adrenergic receptor antagonist, first synthesized in patent US5387603, approved by FDA in 2008, and can be used to treat benign prostatic hyperplasia (BPH) and its Symptoms and signs.

Androgen plays an important role in the occurrence of BPH. There are two forms of androgen in the human body, testosterone and dihydrotestosterone (DHT). The prostate is rich in 5α-reductase, which can convert testosterone into dihydrotestosterone (DHT). The accumulation of dihydrotestosterone (DHT) in the prostate can cause benign prostatic hyperplasia. 5α-reductase inhibitors mainly inhibit the conversion of testosterone to dihydrotestosterone by inhibiting 5α-reductase, block the initiating factors of benign prostatic hyperplasia, and achieve the purpose of preventing benign prostatic hyperplasia. Such drugs include Finasteride (Finasteride), Dutasteride (Dutasteride), etc. Taking 5α-reductase inhibitors in clinical practice often takes 3 months or more to reduce the size of the prostate through drug action, and it takes about 1 year to show the maximum effect. In addition, long-term use may cause some adverse reactions, such as sexual dysfunction (such as ED), decreased libido, ejaculation disorders, infertility, etc. Some patients treated with 5α-reductase inhibitors for BPH exhibit persistent adverse effects even after discontinuation of treatment. Therefore people have put forward higher requirement to the new drug therapy with higher curative effect, lower side effect.

In the prior art, such as Patent Document 1, Patent Document 2, etc., it is disclosed that α1-adrenergic receptor antagonists and 5α-reductase inhibitors are used in combination in the preparation and treatment of dysuria (especially dysuria caused by benign prostatic hyperplasia) and specifically discloses the preparation of silodosin and dutasteride (80:5), and the combination of tasolosin and finasteride or dutasteride, etc. Patent Document 3 discloses that an α1 adrenoceptor blocker (terazosin 5-10 mg) is used in combination with a 5α reductase inhibitor (finasteride 5 mg) to treat benign prostatic hyperplasia. None of the prior art reports on the combined use of silodosin and finasteride and the specific ratio of the two.

Patent Document 1: CN102145003 A

Patent document 2: CN1646135 A

Patent Document 3: WO1992016213

Contents of the invention

The first aspect of the present invention provides a pharmaceutical composition, which comprises silodosin and finasteride. The weight ratio of silodosin and finasteride in the composition is 0.8-8:1; preferably the weight ratio of silodosin and finasteride in the composition is 0.8-4:1; further Preferably the weight ratio of silodosin and finasteride in the composition is 0.8-2:1; more preferably the weight ratio of silodosin and finasteride in the composition is 1-2:1 ; Most preferably, the weight ratio of silodosin and finasteride in the composition is 1.6:1.

The pharmaceutical composition contains silodosin 1-20 mg, specifically, silodosin 1 mg, 2 mg, 3 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, etc. .

The pharmaceutical composition contains finasteride 1-20 mg, specifically, finasteride 1 mg, 2 mg, 3 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, etc. .

Preferably, the pharmaceutical composition contains 4 mg or 8 mg of silodosin;

Preferably, the pharmaceutical composition contains 1 mg or 5 mg of finasteride;

Preferably, the pharmaceutical composition contains 8 mg of silodosin and 1 mg of finasteride.

Preferably, the pharmaceutical composition contains 8 mg of silodosin and 5 mg of finasteride.

Preferably, the pharmaceutical composition contains 4 mg of silodosin and 1 mg of finasteride.

Preferably, the pharmaceutical composition contains 4 mg of silodosin and 5 mg of finasteride.

The second aspect of the present invention provides an oral pharmaceutical preparation, which contains silodosin and finasteride as active ingredients, and further includes pharmaceutically acceptable excipients, which are optionally selected from Excipients, disintegrants, binders, lubricants, diluents, buffers, isotonicity, preservatives, wetting agents, emulsifiers, dispersants, etc.

The preparations can be prepared into oral solid preparations and oral liquid preparations according to conventional methods. Oral preparations can be in the form of tablets, powders, granules, granules, pellets or capsules.

Preferably, the weight ratio of silodosin and finasteride in the oral pharmaceutical preparation is 0.8-8:1; preferably the weight ratio of silodosin and finasteride in the composition is 0.8-4 : 1; more preferably the weight ratio of silodosin and finasteride in the composition is 0.8-2: 1; more preferably the weight ratio of silodosin and finasteride in the composition is 1 -2:1; most preferably the weight ratio of silodosin and finasteride in the composition is 1.6:1. The oral pharmaceutical preparation contains 4 mg or 8 mg of silodosin and/or 1 mg or 5 mg of finasteride.

In a third aspect, the present invention provides a use of a pharmaceutical composition or pharmaceutical preparation comprising silodosin and finasteride in the preparation and treatment of diseases, the diseases being benign prostatic hyperplasia (BPH) or the symptoms and Signs, such as lower urinary tract symptoms (LUTS) associated with BPH.

In the described disease treatment application, the weight ratio containing silodosin and finasteride is 0.8-8:1; preferably the weight ratio of the two is 1-2:1; the most preferred weight ratio is 1.6 :1. In the use, 4 mg or 8 mg of silodosin and/or 1 mg or 5 mg of finasteride are contained.

The present invention unexpectedly finds that the combined use of silodosin and finasteride in a specific ratio enhances the efficacy of each other and has a more significant curative effect than either of the two drugs used alone , the combined use in a specific ratio range achieves an unexpected synergistic effect. And can reduce side effects to a certain extent, such as preventing male erectile dysfunction (ED) and so on.

Detailed ways

The present invention is specifically described by the following examples, but the present invention is not limited to the following examples. The silodosin or finasteride of the present invention further includes pharmaceutically acceptable salts thereof; the experimental animals and experimental materials used in the examples of the present invention are obtained by conventional methods in the art.

Example 1

Evaluation of the effect of silodosin and finasteride on inhibiting phenylephrine-induced contraction of rat prostate smooth muscle.

Male SD rats weighing 300-350 g were selected, and their prostates were removed and transferred to Krebs-Henseleit buffer. The dorsolateral lobe portion of the prostate was separated into prostate gland tissues with a size of 2×10 mm (4 tissues per rat). The dissociated tissue was transferred to an organ bath in Krebs-Henseleit buffer at 37 °C containing 95% _O2 and 5% _CO2 . The two ends of the glandular tissue are respectively fixed on the bottom of the bath and the force sensor, and the force sensor is connected to the polyphysiological recorder. Each tissue was stabilized at 0.2 standard tension for 1 hour and then treated with 10 ^-5 M phenylephrine to induce contraction of the prostate tissue. After the contraction was stabilized, silodosin and/or finasteride or dutasteride were administered according to the dosage regimen in Table 1, and the control group did not receive silodosin and/or finasteride or dutasteride medication. The shrinkage of the control group is 100%, and the shrinkage of the experimental group is calculated [(shrinkage of the experimental group/shrinkage of the control group)×100%]. Data were obtained using four glandular tissues for each group of experiments, and the values are the mean ± standard deviation of shrinkage percentage.

Table 1 Evaluation of relaxation effect on rat prostate tissue

As shown in Table 1, the combination of silodosin and finasteride or silodosin and dutasteride exhibited The effect of relaxing the smooth muscle of the prostate more strongly, and the combined drug has a synergistic effect. Moreover, at the same dosage, the combined use of silodosin and finasteride showed that the combined use of silodosin and dutasteride has a more significant effect on relaxing the smooth muscle of the rat prostate. The combination of silodosin and finasteride was more effective than the combination of silodosin and dutasteride.

When the weight ratio of silodosin and finasteride is 0.8-8:1, the combined drug can achieve a good synergistic effect; preferably the weight ratio of silodosin and finasteride is 0.8-4: 1; further preferably the weight ratio of silodosin and finasteride is 0.8-2:1; more preferably the weight ratio of silodosin and finasteride is 1-2:1; most preferably silodosin The weight ratio with finasteride is 1.6:1, under this ratio, the relaxation effect on rat prostate smooth muscle is the most obvious. The combination of silodosin and finasteride can be used to inhibit the contraction of prostate smooth muscle for the treatment or prevention of BPH and the symptoms and signs caused by it.

Example 2

Effects of silodosin and finasteride on the weight of the rat prostate and the amount of smooth muscle in the penis.

According to the ratio of silodosin and finasteride in the following table 2, fully mix silodosin and finasteride and suspend in CMC-Na (sodium carboxymethylcellulose) to form silodosin Combination of octine and finasteride.

150 male SD rats weighing 300-350 g were selected and randomly divided into 15 groups with 10 rats in each group, which were normal group, control group and experimental group 1-13. Experimental groups 1-13 received subcutaneous injections of the male hormone testosterone propionate (5 mg/kg) dissolved in olive oil every day for 30 consecutive days. At the same time, each rat in the experimental group 1-13 was orally administered the composition of silodosin and/or finasteride every day for 30 consecutive days according to the dosage regimen in the table below. The normal group did not receive testosterone propionate (5 mg/kg) injection, and did not administer silodosin and/or finasteride. The control group only received testosterone propionate (5 mg/kg) injection, and did not receive silodosin and/or finasteride. On the 31st day, the rats were killed, the prostate was collected and weighed, and the PI value of the prostate viscera coefficient [(prostate weight/rat body weight)×100%] was calculated. Collect the rat penis, slice the penis in cross section, stain the section, take images with a digital camera and a stereo microscope, use ImageJ software for parameter measurement, calculate the area of smooth muscle in the cross section of the penis (mm ² ), and use the point counting method The surface density (Sv) of smooth muscle was measured. The results of the PI value of the prostate viscera coefficient, the area of the smooth muscle in the cross-section of the penis and the surface density of the smooth muscle of the rats in each group are expressed as mean ± standard deviation.

Table 2 Effects on the amount of smooth muscle in rat prostate and penis

As shown in Table 2, the combined use of silodosin and finasteride significantly reduced the weight of the prostate gland in rats compared with single drugs, and the combined use achieved a synergistic effect. When finasteride was administered alone, the amount of smooth muscle in the penis of rats decreased significantly. Smooth muscle is the main contractile component of the corpus cavernosum, and in rat animal models, a decrease in the amount of corpus cavernosum smooth muscle is often associated with the development of ED. When silodosin was used in combination with finasteride, it significantly improved the symptoms of decreased smooth muscle mass in the penis of rats. Especially when the combination ratio of silodosin and finasteride in the composition is 8 mg and 5 mg, the reduction effect on rat prostate proliferation is the most obvious, and the combination ratio can completely improve the effect caused by finasteride. Adverse effects of decreased smooth muscle mass in the rat penis.

Therefore, the combined use of silodosin and finasteride can be used to inhibit the proliferation of the prostate gland, can be used to prevent or treat BPH and the symptoms and signs caused by it, and can also be expected to improve the symptoms and signs of BPH caused by finasteride alone. Adverse reactions such as sexual dysfunction (such as ED) caused by treatment.

Example 3

Evaluation of the effect of silodosin and finasteride on prolonging the voiding interval in rats.

24 male rats were selected, randomly divided into 8 groups, 3 rats in each group, and anesthetized with ethyl carbamate. Incision was made along the midline of the abdomen, the ureters on both sides were ligated and cut, and the kidneys were kept open. A cannula is inserted into the bladder through the top of the bladder dome and connected to a tee joint. The other end of the cannula is connected to a pressure transducer to measure intravesical pressure. Continuous instillation of saline into the bladder (3.6mL/h), and continuous instillation of acetic acid solution (0.25%) into the bladder (3.6mL/h) to shorten the urination interval. After obtaining a stable urination interval, measure the urination interval (the time from urination to the next urination) in 3 groups, and take the average value, which is the average urination interval before administration. Experimental groups 1-8 administered silodosin and/or finasteride via femoral vein injection according to the doses in Table 3 below, measured all the times of urination within 30 minutes after administration, and calculated the average urination after administration Interval, evaluate the prolongation rate of the average urination interval before administration [((average urination interval after administration-average urination interval before administration)/(average urination interval before administration))×100%]. The results are shown in Table 3, and the urination interval prolongation rate of each group is represented by mean ± standard deviation.

Table 3 Effects on rat urination interval

serial number	Silodosin (mg/kg)	Finasteride (mg/kg)	Prolongation rate of urination interval (%)
Experimental group 1	4	0	12.7±2.3
Experimental group 2	8	0	26.2±3.1
Experimental group 3	0	1	9.8±2.2
Experimental group 4	0	5	19.1±2.7
Experimental group 5	4	1	48.8±4.5
Experimental group 6	4	5	57.2±4.2
Experimental group 7	8	1	64.5±5.7
Experimental group 8	8	5	75.3±5.2

As shown in Table 3, the combination of silodosin and finasteride significantly prolonged the voiding interval in rats compared with either single agent. The combination of finasteride and silodosin is extremely effective in the prevention or treatment of urinary frequency or incontinence and is indicated for the treatment or prevention of BPH and the signs and symptoms it causes.

Claims (10)

1. A pharmaceutical composition containing silodosin and finasteride as active ingredients.
2. The pharmaceutical composition according to claim 1, wherein the weight ratio of silodosin and finasteride is 0.8-8:1.
3. The pharmaceutical composition according to claim 1, wherein the weight ratio of silodosin and finasteride is 0.8-4:1; preferably the weight ratio is 0.8-2:1.
4. The pharmaceutical composition according to claim 1, wherein the weight ratio of silodosin and finasteride is 1.6:1.
5. The pharmaceutical composition according to claim 1, which contains 4 mg or 8 mg of silodosin and/or 1 mg or 5 mg of finasteride.
6. A kind of oral pharmaceutical preparation, described preparation contains silodosin and finasteride as active component, and pharmaceutically acceptable adjuvant, in described preparation, the weight ratio of silodosin and finasteride is 0.8-8:1.
7. The pharmaceutical preparation according to claim 6, which contains 4 mg or 8 mg of silodosin and/or 1 mg or 5 mg of finasteride.
8. Use of the pharmaceutical composition according to claim 1 in the preparation of medicines for treating benign prostatic hyperplasia and the symptoms and signs thereof.
9. purposes according to claim 8, wherein the weight ratio of silodosin and finasteride is 1.6:1.
10. The use according to claim 8, which contains silodosin 8mg and finasteride 5mg.