CN107714704A - 30 sour chewable tablets of silaenafil and 2 methoxyl group, 3 oxo, 18 β oleananes, 1,12 diene - Google Patents
30 sour chewable tablets of silaenafil and 2 methoxyl group, 3 oxo, 18 β oleananes, 1,12 diene Download PDFInfo
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- CN107714704A CN107714704A CN201710848111.1A CN201710848111A CN107714704A CN 107714704 A CN107714704 A CN 107714704A CN 201710848111 A CN201710848111 A CN 201710848111A CN 107714704 A CN107714704 A CN 107714704A
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- Prior art keywords
- silaenafil
- chewable tablets
- diene
- methoxyl group
- sour
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- 0 CC(C)([C@](*)(CC[C@]1(*)[C@]2(*)CC=C3[C@](*)(C[C@](C)(CC4)C(O)=O)C4(C)CC[C@@]13C)[C@]2(C)C=C1*)C1=* Chemical compound CC(C)([C@](*)(CC[C@]1(*)[C@]2(*)CC=C3[C@](*)(C[C@](C)(CC4)C(O)=O)C4(C)CC[C@@]13C)[C@]2(C)C=C1*)C1=* 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
30 sour chewable tablets of silaenafil and 2 methoxyl group, 3 oxo, 18 β oleananes, 1,12 diene, it is characterized in that described chewable tablets forms by active component and suitable for the pharmaceutic adjuvant of chewable tablets, described active component is that mass ratio is 1:1.2~1.5 silaenafil and the β oleananes 1 of 2 methoxyl group, 3 oxo 18,12 diene 30 is sour (I), and 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
Technical field：
The present invention relates to a kind of silaenafil and -18 β of 2- methoxyl group -3- oxos-oleanane -1,12- diene -30- acid
Compound preparation.
Background technology：
Silaenafil (Sildenafil CAS：It is 139755-83-2) a kind of selective PDE5 inhibitor, it is public by Pfizer
Department's exploitation, is listed in March, 1998, as the first treatment ED oral drugs, the work for the suppression PDE5 that it can be selective
Property, the level of cGMP (cyclic guanylic acid) in CC (corpus cavernosa, corpora cavernosa penis) smooth muscle is improved, so as to realize pair
ED treatment.However, because PDE5 in human body other positions also has part expression, and silaenafil is also deposited to PDE3, PDE6 etc.
In certain inhibitor activity, therefore silaenafil can produce the pairs such as headache, flush, indigestion, dysopia in use
Effect, and commonly required dosage be 50-100mg during for ED treatments, larger dosage can increase side effect probability of happening and
The order of severity, therefore the bioavilability of silaenafil is improved, its therapeutic effect is improved, reduces side effect as answering it
The improved main purpose in side.
Chinese patent CN201110131028.5 discloses the 2- methoxyl group -3- oxygen as a kind of Enoxolone derivative
- 18 β of generation-oleanane -1,12- diene -30- is sour (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
The content of the invention
The invention provides a kind of silaenafil and -18 β of 2- methoxyl group -3- oxos-oleanane -1,12- diene -30-
The compound chewable tablets of sour (I), under study for action we have surprisingly found that, using a certain proportion of compound (I) and silaenafil and
Its manufactured compound oral administration preparation, its therapeutic effect can be significantly improved, reduce the once used amount of silaenafil, so as to
Reduce the generation of its side effect.
The invention provides a kind of compound silaenafil chewable tablets, it is characterized in that described chewable tablets is by active component and fits
Pharmaceutic adjuvant for chewable tablets forms, and described active component is that mass ratio is 1:1.2~1.5 silaenafil and 2- methoxies
- 18 β of base -3- oxos-oleanane -1,12- diene -30- is sour (I), and described pharmaceutic adjuvant is by accounting for pharmaceutic adjuvant gross mass 3-
4% disintegrant, 3-5% adhesive, 0.5-3% flavouring, the filler composition of 0.5-1% lubricant and surplus.
Described chewable tablets, it is characterised in that the every silaenafil containing 15~25mg.
Described chewable tablets, it is characterised in that the disintegrant is selected from microcrystalline cellulose, low substituted hydroxy-propyl fiber, crosslinking
One or more in sodium carboxymethylcellulose, PVPP, crosslinked carboxymethyl fecula sodium.Preferred weight ratio 1:
1~1.5 PVPP and low-substituted hydroxypropyl cellulose (HPC).
Described filler, selected from lactose, sorbierite, mannitol.It is preferred that mannitol
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 1：1~1.2 polyvinylpyrrolidone (PVP) and hydroxypropyl methyl cellulose
The lubricant includes but are not limited to superfine silica gel powder, magnesium stearate, talcum powder, Cab-O-sil, Arosil, water
Close sial magnesium stearate, calcium stearate, zinc stearate, single stearic acid glycerine lipoprotein, polyethylene glycol, hydrogenated vegetable oil, stearic rich horse
Sour sodium, polyoxyl 40 stearate, single bay sucrose acid ester, sldium lauryl sulfate, magnesium laurylsulfate, dodecyl sulphate
Magnesium and talcum powder etc., 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, menthol, preferred weight ratio 1:0.8~0.9 xanthans and
Guar gum.
Although under study for action it was found that -18 β of 2- methoxyl group -3- oxos-oleanane -1,12- diene -30- acid itself
There is no the effect of PDE5 inhibitor, but silaenafil and -18 β of 2- methoxyl group -3- oxos-oleanane -1,12- diene -30- acid
(I) compound oral administration preparation of composition, selectivity when can significantly improve silaenafil as PDE5 inhibitor, so as to drop
Its low adverse reaction, and shown according to zoopery, when compound (I) is administered with silaenafil with preferable proportion,
Its therapeutic effect to ED animal patterns can be improved.Illustrate chewable tablets provided by the invention, by optimization formula, can reduce
The selectivity of silaenafil is improved, reduces its side effect, and the anti-ED effects of silaenafil can be significantly improved.
Embodiment
All formulations example (every auxiliary material 200mg, common 200g) in terms of 1000
Preparation example 1~4, silaenafil 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.
Pharmacological Examples 1PDEs Choice tests
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 silaenafil 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 silaenafil 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 silaenafil, real
8,9 solution of group are tested as silaenafil 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 silaenafil 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 silaenafil 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) silaenafil 10mg/kg |
| 3 | Silaenafil 10mg/kg+ compounds (I) 10mg/kg |
| 4 | Silaenafil 10mgkg+ compounds (I) 12mg/kg |
| 5 | Silaenafil 10mg/kg+ compounds (I) 15mg/kg |
| 6 | Silaenafil 10mg/kg+ compounds (I) 20mg/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 and its time of measuring are recorded, as a result see the table below
Test result indicates that when silaenafil and compound (I) are with 1:When 1.2~1.5 ratio is administered simultaneously, Ke Yixian
Write improve under the conditions of auricular vein drug administration by injection SNP Conscious Rabbit the degree of erection, so as to improve silaenafil for
ED therapeutic effect, and the effect only can just be embodied when using above-mentioned preferred proportion scope, more or less chemical combination
Thing (I) is without this effect.
Claims (3)
1. silaenafil and -18 β of 2- methoxyl group -3- oxos-oleanane -1,12- diene -30- acid chewable tablets, it is characterized in that institute
The chewable tablets stated forms by active component and suitable for the pharmaceutic adjuvant of chewable tablets, and described active component is that mass ratio is 1:
1.2~1.5-18 β of silaenafil and 2- methoxyl group-3- oxos-oleanane-1,12- diene-30- is sour (I), described medicine
With auxiliary material by accounting for pharmaceutic adjuvant gross mass 3-4% disintegrant, 3-5% adhesive, 0.5-3% flavouring, 0.5-1%
Lubricant and the filler of surplus composition.
2. chewable tablets as claimed in claim 1, it is characterised in that the every silaenafil containing 15~25mg.
3. chewable tablets as claimed in claim, it is characterised in that the disintegrant is selected from weight than 1:1~1.5 poly- second of crosslinking
Alkene pyrrolidone and low-substituted hydroxypropyl cellulose (HPC), the preferred mannitol of described filler, described adhesive are selected from weight
Than 1：1~1.2 polyvinylpyrrolidone (PVP) and hydroxypropyl methyl cellulose, the preferred magnesium stearate of lubricant are described
Flavouring is selected from weight than 1:0.8~0.9 xanthans and guar gum.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710848111.1A CN107714704A (en) | 2017-09-19 | 2017-09-19 | 30 sour chewable tablets of silaenafil and 2 methoxyl group, 3 oxo, 18 β oleananes, 1,12 diene |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710848111.1A CN107714704A (en) | 2017-09-19 | 2017-09-19 | 30 sour chewable tablets of silaenafil and 2 methoxyl group, 3 oxo, 18 β oleananes, 1,12 diene |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107714704A true CN107714704A (en) | 2018-02-23 |
Family
ID=61207573
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710848111.1A Pending CN107714704A (en) | 2017-09-19 | 2017-09-19 | 30 sour chewable tablets of silaenafil and 2 methoxyl group, 3 oxo, 18 β oleananes, 1,12 diene |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107714704A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999002147A1 (en) * | 1997-07-09 | 1999-01-21 | Androsolutions, Inc. | Improved methods and compositions for treating male erectile dysfunction |
| CN102250189A (en) * | 2011-05-20 | 2011-11-23 | 中国药科大学 | Glycyrrhetic acid derivative with 1, 12-diene-3-ketone skeleton, its preparation method and medicinal uses |
-
2017
- 2017-09-19 CN CN201710848111.1A patent/CN107714704A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999002147A1 (en) * | 1997-07-09 | 1999-01-21 | Androsolutions, Inc. | Improved methods and compositions for treating male erectile dysfunction |
| CN102250189A (en) * | 2011-05-20 | 2011-11-23 | 中国药科大学 | Glycyrrhetic acid derivative with 1, 12-diene-3-ketone skeleton, its preparation method and medicinal uses |
Non-Patent Citations (1)
| Title |
|---|
| 高传玉 等: "《实用心血管药物学》", 31 August 2014, 郑州大学出版社 * |
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| PB01 | Publication | ||
| PB01 | Publication | ||
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| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180223 |
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| RJ01 | Rejection of invention patent application after publication |