CN107595855A

CN107595855A - Vardenafil oral formulations

Info

Publication number: CN107595855A
Application number: CN201710941413.3A
Authority: CN
Inventors: 陈有平
Original assignee: Individual
Current assignee: Individual
Priority date: 2017-10-11
Filing date: 2017-10-11
Publication date: 2018-01-19

Abstract

Vardenafil oral formulations, it is characterized in that described oral formulations are chewable tablets, the chewable tablets forms by active component and suitable for the pharmaceutic adjuvant of chewable tablets, described active component is Vardenafil and the β oleananes 1 of 2 cyano group, 3 oxo 18, the nitrile of 12 diene 30 (I), the every Vardenafil containing 5~10mg, 10~15mg compounds (I)；Described pharmaceutic adjuvant is made up of the filler for accounting for the disintegrant of pharmaceutic adjuvant gross mass 3 4%, 3 5% adhesive, 0.5 3% flavouring, 0.5 1% lubricant and surplus.

Description

Vardenafil oral formulations

Technical field：

The present invention relates to a kind of Vardenafil and the compound oral administration preparation of Enoxolone derivative.

Background technology：

Vardenafil (Vardenafil) is a kind of selective PDE5 inhibitor, by Bayer Bitterfeld GmbH (Bayer) and Ge Lansu SmithKline (Glaxo Smith Kline) company develops, and compared with silaenafil, it has, and dosage is few, and onset time is express, safety The characteristics of property is high, Chinese patent CN201110131028.5 discloses the 2- cyano group -3- oxygen as a kind of Enoxolone derivative Generation -18 β-oleanane -1,12- diene -30- nitriles (I), and it has certain antitumor activity, but in the publication, the chemical combination The antitumor activity and unobvious of thing.The chemical formula of the compound (I) is

We have found that compound (I) can increase the selective depression to PDE5 to Vardenafil in pilot experiments, therefore A kind of properly mixed Enoxolone derivative and Vardenafil compound preparation are provided on the basis of this to be turned into the prior art urgently Solve the problems, such as.

The content of the invention

The invention provides a kind of Vardenafil and -18 β of 2- cyano group -3- oxos-oleanane -1,12- diene -30- nitriles (I) compound oral administration preparation, under study for action we have surprisingly found that, using a certain proportion of compound (I) and Vardenafil and Its manufactured compound oral administration preparation, its therapeutic effect can be significantly improved, reduce the once used amount of Vardenafil, so as to Reduce the generation of its side effect.

The invention provides a kind of Vardenafil oral formulations, it is characterized in that described oral formulations are chewable tablets, it is described Chewable tablets forms by active component and suitable for the pharmaceutic adjuvant of chewable tablets, and described active component is Vardenafil and 2- cyanogen - 18 β of base -3- oxos-oleanane -1,12- diene -30- nitriles (I), the every Vardenafil containing 5~10mg, 10~15mg Compound (I)；Described pharmaceutic adjuvant is by accounting for pharmaceutic adjuvant gross mass 3-4% disintegrant, 3-5% adhesive, 0.5-3% Flavouring, 0.5-1% lubricant and surplus filler composition.

Described chewable tablets, it is characterised in that the disintegrant be selected from microcrystalline cellulose, low substituted hydroxy-propyl fiber, hand over Join the one or more in polyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium.Preferred weight ratio 1:0.4~0.6：0.3~0.5 PVPP (cross-linked pvp), Ac-Di-Sol (crosslinking CMC-Na) and microcrystalline cellulose.

Described filler, selected from lactose, sorbierite, mannitol.It is preferred that lactose.

Described adhesive is selected from starch, pregelatinized starch, dextrin, maltodextrin, sucrose, Arabic gum, polyethylene Alcohol, polyethylene glycol, polyvinylpyrrolidone (PVP), alginic acid and alginate, xanthans, hydroxypropyl cellulose and hydroxypropyl Methylcellulose (HPMC), preferably weight is than 1：0.6~0.8：0.2~0.3 polyvinylpyrrolidone (PVP), pregelatinated Starch and hydroxypropyl methyl cellulose

The lubricant is preferably magnesium stearate.

The flavouring is selected from sucrose, saccharin sodium, honey element, Aspartame, citric acid, tartaric acid, malic acid, Vitamin C One or more in acid, xanthans, guar gum, tragacanth, preferred weight ratio 1:0.2~0.3 sucrose and citric acid.

Although under study for action it was found that 2- cyano group -3- oxos -18 β-oleananes-as Enoxolone derivative 1,12- diene -30- nitriles (I) itself without PDE5 inhibitor effect, but with Vardenafil composition compound oral administration preparation, can To significantly improve Vardenafil as selectivity during PDE5 inhibitor, so as to reduce its adverse reaction, and according to animal Experiment shows, when compound (I) is administered with Vardenafil with preferable proportion, can improve it to ED animal patterns Therapeutic effect.Illustrate chewable tablets provided by the invention, by optimization formula, the selectivity of Vardenafil can be improved, reduce it Side effect, in the treatment for diseases such as ED and pulmonary hypertensions, its therapeutic effect can be significantly improved..

Embodiment

All formulations example (every auxiliary material 200mg, common 200g) in terms of 1000

Preparation example 1~4, Vardenafil and -18 β of 2- methoxyl group -3- oxos-oleanane -1,12- diene -30- acid (letters Claim compound (I)) compound chewable tablets

The chemical formula of compound (I) is as follows

The synthetic method of compound (I) is as described in CN201110131028.5.

The compound method of chewable tablets is as follows in preparation example：

(1) in prescription ratio, part supplementary material (main ingredient, adhesive, filler and disintegrant) is accurately weighed, crosses 100 mesh Sieve, thoroughly mixing, the appropriate amount of ethanol for adding 50% prepares softwood, is pelletized with 24 mesh sieves, 60 DEG C of dryings, then with 24 mesh sieve whole grains.

(2) flavouring and lubricant are added in the particle after above-mentioned whole grain, is sufficiently mixed uniformly, trimmer weight, tabletting.

The PDEs Choice tests of Pharmacological Examples 1

PDE6 extracts from bovine retina, and PDE3 and PDE5 extract from rabbit platelet, and PDE4 extracts from male SD rat kidney, PDE1 extracts from male SD rat Cerebral cortex, and PDE2 extracts from beasle dog adrenal gland

PDEs activity test methods

The storing solution for being respectively l00mM with DMSO compound concentrations by Vardenafil and compound (I), then shown according to the form below Ratio dilutes the mixed solution of the obtained compound (I) of experimental group 1~7 and Vardenafil with purified water, experimental group 1~7 Mixed solution concentration is respectively l0mM, 1mM, 100 μM, l0 μM, 1 μM, l00nM, l0nM, 1nM, 0.1nM in terms of Vardenafil, real 8,9 solution of group are tested as Vardenafil and compound (I) storing solution are diluted into l0mM, 1mM, 100 μM, l0 μ with purified water respectively M, 1 μM, the solution of l00nM, l0nM, 1nM, 0.1nM concentration.

According to different enzymes, different drug concentration gradients is selected, measure various concentrations suppress to live to the inhibitory activity of enzyme Property calculates according to equation below.

In formula, CPMsample represents to contain testing compound in the buffer solution of kit simultaneously, enzyme and hydrolysis substrate When read-out count value, CPMcontrol represented in buffer solution to the count value read-out by containing enzyme and hydrolysis substrate, The count value read-out by hydrolysis substrate is comprised only in CPMblank buffer solutions.

IC50 (half maximal inhibitory are calculated by Prism softwares nonlinear regression concentration)。

Packet and composition ratio situation such as following table (using Vardenafil weight as 100)

Experimental result is as follows

Test result indicates that it is right to significantly improve its when compound (I) is coordinated with Vardenafil with certain proportion PDE5 selectivity.

Effect experiment in the body of Pharmacological Examples 2

2.1. animal packet

Using male mature rabbits, body weight 3.5-4.5kg, random packet, every group 10, packet is seen below with administrations Table：

Group number	Administrations
		1	(blank control) physiological saline 4ml/kg
2	(positive control) Vardenafil 10mg/kg
		3	Vardenafil 5mg/kg+ compounds (I) 5mg/kg
4	Vardenafil 5mgkg+ compounds (I) 10mg/kg
		5	Vardenafil 5mg/kg+ compounds (I) 15mg/kg
6	Compound (I) 10mg/kg

2.3 method of testing

SNP (sodium nitroprussiate) as external source type NO donors is auricular vein drug administration by injection, and capacity 1ml/kg, parenteral solution is administered SNP concentration be 0.1 μm of ol/L.

After rabbit is weighed, dosage regimen in capacity foregoing 2.1 is administered by 4ml/kg and carries out carry out gastric infusion, and in gavage The laggard rows of 1h are administered and carry out SNP auricular vein injections, 5,10,15,30,45 measurement penis length (exposed portion) after injection, and Penis length maximum is recorded, as a result see the table below

Test result indicates that when Vardenafil and compound (I) are with 1:, can be notable when 1.5~2 ratio is administered simultaneously The degree of erection of the Conscious Rabbit under the conditions of auricular vein drug administration by injection SNP is improved, so as to improve Vardenafil for ED Therapeutic effect, and the effect only using above-mentioned preferred proportion scope when can just be embodied, more or less compounds (I) without this effect, and simultaneously effect in the case of compound alone (I).

Claims

1. Vardenafil oral formulations, it is characterized in that described oral formulations are chewable tablets, the chewable tablets by active component and Formed suitable for the pharmaceutic adjuvant of chewable tablets, described active component is Vardenafil and 2- cyano group -3- oxos -18 β-olive Alkane -1,12- diene -30- nitriles (I), the every Vardenafil containing 5~10mg, 10~15mg compounds (I)；Described is medicinal Auxiliary material is by accounting for pharmaceutic adjuvant gross mass 3-4% disintegrant, 3-5% adhesive, 0.5-3% flavouring, 0.5-1% profit Lubrication prescription and the filler of surplus composition.

2. Vardenafil oral formulations as claimed in claim 1, it is characterised in that the disintegrant is selected from weight than 1:0.4~ 0.6：0.3~0.5 PVPP (cross-linked pvp), Ac-Di-Sol (crosslinking CMC-Na) and micro- Crystalline cellulose.

3. Vardenafil oral formulations as claimed in claim 1, it is characterised in that the preferred lactose of described filler.

4. Vardenafil oral formulations as claimed in claim 1, it is characterised in that described adhesive is preferably weight than 1：0.6 ~0.8：0.2~0.3 polyvinylpyrrolidone (PVP), pregelatinized starch and hydroxypropyl methyl cellulose.

5. Vardenafil oral formulations as claimed in claim 1, it is characterised in that the lubricant is preferably magnesium stearate.

6. Vardenafil oral formulations as claimed in claim 1, it is characterised in that the flavouring preferred weight ratio 1:0.2~ 0.3 sucrose and citric acid.