CN108126203A - A kind of pharmaceutical composition and its drug delivery system and purposes - Google Patents
A kind of pharmaceutical composition and its drug delivery system and purposes Download PDFInfo
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- CN108126203A CN108126203A CN201810010260.5A CN201810010260A CN108126203A CN 108126203 A CN108126203 A CN 108126203A CN 201810010260 A CN201810010260 A CN 201810010260A CN 108126203 A CN108126203 A CN 108126203A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
- A61K31/33—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
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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Abstract
A kind of pharmaceutical composition, effective ingredient are mainly made of clomipramine hydrochloride and Na Fei class drugs.In effective ingredient, the mass ratio that clomipramine hydrochloride accounts for the two is 0.1：1~10.That non-class drug is Vardenafil hydrochloric acid either sildenafil citrate or tadalafil.The present invention also provides the drug delivery systems and purposes of foregoing pharmaceutical composition.On the basis of having active constituents of medicine, new screening obtains a kind of active constituents of medicine composition and is suitble to the pharmaceutical preparation of the combination present invention, and improve premature ejaculation for exploitation lays the foundation with the drug of erectile dysfunction.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and its drug delivery systems, and the invention further relates to the use of the pharmaceutical composition
On the way.
Background technology
In sex dysfunction patient, there is premature ejaculation with erectile dysfunction in some patientss, anti-premature ejaculation is used alone
Drug or treatment erectile dysfunction drug, are difficult to promote life quality.
Clomipramine hydrochloride（Clomipramine Hydrochloride）For a kind of safe and reliable antidepression listed
Medicine, existing researcher have found that this product can have effects that deferring male premature ejaculation, and start by inhibiting the reuptake of 5-HT
The anti-premature ejaculation drug development of clomipramine etc..Sildenafil citrate（Sildenafil Citrate ）, Vardenafil hydrochloric acid
（Vardenafil hydrochloride）, tadalafil（Calais ）It has been listed that, for treating penile erectile function barrier
That the non-class drug hindered.
There has been no clomipramine hydrochlorides and sildenafil citrate or clomipramine hydrochloride and Vardenafil hydrochloric acid at present
Either clomipramine hydrochloride and two single of tadalafil are medication combined or the research that is used into compound is reported.
Invention content
The technical problems to be solved by the invention are in view of the deficiencies of the prior art, to provide a kind of new sexual function that is directed to and hinder
Hinder active constituent compound medicament composition of patient's premature ejaculation with the bad problem of erection function.
Another technical problem to be solved by this invention be to provide more than compound medicament composition complete active constituent
Deliver the applicable preparation taken.
There is provided the purposes of foregoing pharmaceutical composition for another technical problem to be solved by this invention.
The technical problems to be solved by the invention are realized by following technical solution.The present invention is a kind of drug
Composition, its main feature is that：Its effective ingredient is mainly made of clomipramine hydrochloride and Na Fei class drugs.The present invention's is main effective
Composition uses compound, and in effective ingredient, the mass ratio that both clomipramine hydrochloride accounts for is 0.1：1~10.Described that
Non- class drug is preferably Vardenafil hydrochloric acid either sildenafil citrate or tadalafil.
In the present composition, in addition to the raw material of 2 kinds of main ingredient, any of pharmacy or clinical license can also be added
A kind of pharmaceutic adjuvant.
Another technical problem to be solved by this invention is further realized by following technical solution.This hair
It is bright to also disclose a kind of drug delivery system of the pharmaceutical composition as described in above technical scheme, its main feature is that：The drug is passed
Send system can be pharmaceutically acceptable preparation, preferably Orally dissolving film either soft capsule or control sustained release preparation.
Drug delivery system of the present invention, further preferred technical solution are：The Orally dissolving film
In, clomipramine hydrochloride raw material and Na Fei class raw materials crushed 400 mesh sieve, i.e. raw material particle size≤38 μm, with hydroxypropyl methyl fibre
Dimension element or low-substituted hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, hyaluronic acid, Polyvinylcaprolactame-poly-vinegar acid second
Enester-ethylene glycol copolymer, polyethylene oxide, cellulose acetate, polyvinylpyrrolidone, polymethylacrylic acid-methyl-prop
Olefin(e) acid ester-methacrylic acid, hypromellose phthalate, ethyl cellulose, cellulose acetate-butyrate, secondary amine epoxy
One or both of resin, methacrylic acid trimethylammonium ethyl ester methacrylate copolymer ingredient prepares film load jointly
Body.
Drug delivery system of the present invention, further preferred technical solution are：Clomipramine hydrochloride raw material and
That non-class medicine material crushed 200 mesh sieve, i.e. raw material particle size≤75 μm, filling in gelatin, sweet using vegetable oil as dispersion
Oil and water are made for main material in soft capsule, and soft capsule is made.
Drug delivery system of the present invention, further preferred technical solution are：Saliferous in each preparation unit
Sour clomipramine 5mg~25mg, 25~50mg of silaenafil；Or hydrochloric clomipramine 5mg~25mg, tadalafil 5mg
~10mg；Or containing sour clomipramine 5mg~25mg, Vardenafil hydrochloric acid 5mg~10mg.
Drug delivery system of the present invention, further preferred technical solution are：It is with hydrochloric acid to control sustained release preparation
Clomipramine A and that non-class B raw material are respectively or the quick-release delivering body that is mixed and/or non-with that by clomipramine hydrochloride A
Class B respectively or be mixed sustained release delivery body composition；The particle size range 150 μm ~ 38 of clomipramine hydrochloride, that non-class raw material
μm；
Including：（1）Immediate-release granules are made in A, and immediate-release granules are made in B, are then pressed into double-layer tablets；Alternatively, take A that quick-release is made
Grain, part B are made immediate-release granules, are pressed into A+B quick-release double-layer tablets, while part B is taken to be prepared into sustained release tablets, the two are packed into same
One hard shell capsules；Alternatively, taking part A that immediate-release granules are made, immediate-release granules are made in part B, are pressed into A+B quick-release double-layer tablets, simultaneously
Part A, B is taken to prepare sustained release tablets respectively and is pressed into A+B sustained-release double-layer tablets, the two is fitted into same hard shell capsules；Or take A systems
Into immediate-release granules, A fast-release tablets are pressed into, while take B that immediate-release granules and slow-releasing granules are respectively prepared, and are pressed into B double-layer tablets, so
A fast-release tablets and B double-layer tablets are fitted into same hard shell capsules afterwards；Alternatively, taking A that immediate-release granules and slow-releasing granules are respectively prepared, suppress
It into A double-layer tablets, while takes B that immediate-release granules and slow-releasing granules are respectively prepared, and is developed into B double-layer tablets, then by A double-layer tablets and B
Double-layer tablets are fitted into same hard shell capsules；
（2）A, control sustained release pellet is respectively prepared in the control spansule or A, B that B is mixed, then mixing dress hard shell capsules；
（3）B sustained release tablets are prepared with part B, using B sustained release tablets as the piece heart, A and part B are taken to mix, coating material or compacting packet is made
Clothing layer particle, is coated B sustained release tablets, and the tablet or piece heart is tabletted together with pressed coated layer particle is made；Or
Person is mixed with AB sustained release tablets with part A and part B, using AB sustained release tablets as the piece heart, part A and part B is taken to mix, packet is made
Clothing material or pressed coated layer particle, are coated AB sustained release tablets, tablet are made or by the piece heart and pressed coated layer particle one
It rises tabletted.
Drug delivery system of the present invention, further preferred technical solution are：Its quick-release of each preparation unit
Part clomipramine hydrochloride content 5mg~25mg, 15 mg of slow-released part clomipramine hydrochloride content~50mg, each preparation list
The mg of position clomipramine hydrochloride content≤75；Each preparation unit that non-25~50mg of content of its immediate release section, slow-released part citron
25~50mg of sour silaenafil content, the mg of each preparation unit sildenafil citrate content≤100；Alternatively, immediate release section salt
5~10mg of sour Vardenafil content, 5~10mg of slow-released part Vardenafil hydrochloric acid content, each preparation unit hydrochloric acid cut down ground that
The mg of non-content≤20；Alternatively, immediate release section tadalafil 5~10mg of content, slow-released part tadalafil 5~10mg of content, often
The mg of one preparation unit tadalafil content≤20.
Pharmaceutical composition of the present invention can extend male's sexual life time drug preparing.
Compared with prior art, for the present invention on the basis of having active constituents of medicine, new screening obtains a kind of pharmaceutical activity
Component composition and the pharmaceutical preparation for being suitble to the combination improve premature ejaculation for exploitation and are established with the drug of erectile dysfunction
Basis.
Specific embodiment
The specific technical solution of the present invention described further below, in order to which those skilled in the art is further understood that
The present invention, without forming the limitation to its right.
Embodiment 1, a kind of pharmaceutical composition, effective ingredient are mainly made of clomipramine hydrochloride and Na Fei class drugs.
In effective ingredient, the quality that clomipramine hydrochloride accounts for the two is 1：1.That non-class drug is Vardenafil hydrochloric acid or citric acid west
That non-or tadalafil of ground.The drug delivery system is oral quick-dissolving film preparation, in the Orally dissolving film, hydrochloric acid chlorine rice
The bright raw material of pa and Na Fei class raw materials crushed 400 mesh sieve, i.e. raw material particle size≤38 μm, with hydroxypropyl methyl cellulose or low take
For hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, hyaluronic acid, Polyvinylcaprolactame-polyvinyl acetate-poly- second two
Alcohol copolymer, polyethylene oxide, cellulose acetate, polyvinylpyrrolidone, polymethylacrylic acid-methyl acrylate-methyl
Acrylic acid, hypromellose phthalate, ethyl cellulose, cellulose acetate-butyrate, secondary amine epoxy resin, methyl-prop
One or both of olefin(e) acid trimethylammonium ethyl ester methacrylate copolymer ingredient, prepares membrane carrier jointly.
Embodiment 2, a kind of pharmaceutical composition, effective ingredient are mainly made of clomipramine hydrochloride and Na Fei class drugs.
In effective ingredient, the quality that clomipramine hydrochloride accounts for the two is 0.1：10.It is other same as Example 1.
Embodiment 3, a kind of pharmaceutical composition, effective ingredient are mainly made of clomipramine hydrochloride and Na Fei class drugs.
In effective ingredient, the quality that clomipramine hydrochloride accounts for the two is 1：10.That non-class drug is Vardenafil hydrochloric acid or citric acid
Silaenafil or tadalafil.The drug delivery system is soft capsule, and preparation method is to take clomipramine hydrochloride raw material and Na Fei
Class medicine material crushed 200 mesh sieve, i.e. raw material particle size≤75 μm, using vegetable oil as dispersion, it is filling in gelatin, glycerine and
Water is made for main material in soft capsule, and soft capsule is made.
Embodiment 4, a kind of pharmaceutical composition, effective ingredient are mainly made of clomipramine hydrochloride and Na Fei class drugs.
In effective ingredient, the quality that clomipramine hydrochloride accounts for the two is 5：10.It is other same as Example 3.
Embodiment 5, a kind of pharmaceutical composition, effective ingredient are mainly made of clomipramine hydrochloride and Na Fei class drugs.
The drug delivery system is control sustained release preparation.Hydrochloric clomipramine 5mg~25mg in each preparation unit, silaenafil 25~
50mg；Control sustained release preparation be with clomipramine hydrochloride A and that non-class B raw material respectively or the quick-release that is mixed delivers body, with/
Or by clomipramine hydrochloride A and that non-class B respectively or the sustained release delivery body that is mixed forms；Clomipramine hydrochloride, that is non-
150 μm ~ 38 μm of the particle size range of class raw material；
Its step is：（1）Immediate-release granules are made in A, and immediate-release granules are made in B, are then pressed into double-layer tablets；Alternatively, take A that quick-release is made
Immediate-release granules are made in particle, part B, are pressed into A+B quick-release double-layer tablets, while part B is taken to be prepared into sustained release tablets, the two is packed into
Same hard shell capsules；Alternatively, taking part A that immediate-release granules are made, immediate-release granules are made in part B, are pressed into A+B quick-release double-layer tablets, together
When part A, B is taken to prepare sustained release tablets respectively and is pressed into A+B sustained-release double-layer tablets, the two is fitted into same hard shell capsules；Or take A
Immediate-release granules are made, are pressed into A fast-release tablets, while take B that immediate-release granules and slow-releasing granules are respectively prepared, and are pressed into B double-layer tablets,
Then A fast-release tablets and B double-layer tablets are fitted into same hard shell capsules；Alternatively, taking A that immediate-release granules and slow-releasing granules are respectively prepared, press
A double-layer tablets are made, while take B that immediate-release granules and slow-releasing granules are respectively prepared, and are developed into B double-layer tablets, then by A double-layer tablets with
B double-layer tablets are fitted into same hard shell capsules.
Embodiment 6, a kind of pharmaceutical composition, effective ingredient are mainly made of clomipramine hydrochloride and Na Fei class drugs.
The drug delivery system is control sustained release preparation.Hydrochloric clomipramine 5mg~25mg, tadalafil 5mg in each preparation unit
~10mg.
Control sustained release preparation be with clomipramine hydrochloride A and that non-class B raw material respectively or the quick-release that is mixed delivers body,
And/or by clomipramine hydrochloride A and that non-class B respectively or the sustained release delivery body that is mixed forms；Clomipramine hydrochloride, that
150 μm ~ 38 μm of the particle size range of non-class raw material；
A, control sustained release pellet is respectively prepared in the control spansule or A, B that B is mixed, then mixing dress hard shell capsules.
Embodiment 7, a kind of pharmaceutical composition, effective ingredient are mainly made of clomipramine hydrochloride and Na Fei class drugs.
The drug delivery system is control sustained release preparation.Containing sour clomipramine 5mg~25mg, Vardenafil hydrochloric acid in each preparation unit
5mg~10mg.
Control sustained release preparation be with clomipramine hydrochloride A and that non-class B raw material respectively or the quick-release that is mixed delivers body,
And/or by clomipramine hydrochloride A and that non-class B respectively or the sustained release delivery body that is mixed forms；Clomipramine hydrochloride, that
150 μm ~ 38 μm of the particle size range of non-class raw material；
B sustained release tablets are prepared with part B, using B sustained release tablets as the piece heart, A and part B is taken to mix, coating material or pressed coated is made
Layer particle, is coated B sustained release tablets, the tablet or piece heart is tabletted together with pressed coated layer particle is made；Alternatively,
AB sustained release tablets are mixed with part A and part B, using AB sustained release tablets as the piece heart, part A and part B is taken to mix, coating material is made
Material or pressed coated layer particle, are coated AB sustained release tablets, tablet are made or presses the piece heart together with pressed coated layer particle
Piece is made.
Embodiment 8, a kind of pharmaceutical composition, effective ingredient are mainly made of clomipramine hydrochloride and Na Fei class drugs.
The drug delivery system is control sustained release preparation.Each preparation unit its immediate release section clomipramine hydrochloride content 5mg~25mg delays
Release part 15 mg of clomipramine hydrochloride content~50mg, the mg of each preparation unit clomipramine hydrochloride content≤75；Each system
That non-25~50mg of content of its immediate release section of agent unit, slow-released part 25~50mg of sildenafil citrate content, each preparation
The mg of unit sildenafil citrate content≤100；Alternatively, immediate release section Vardenafil hydrochloric acid 5~10mg of content, slow-released part
5~10mg of Vardenafil hydrochloric acid content, the mg of each preparation unit Vardenafil hydrochloric acid content≤20；Alternatively, immediate release section he reach
That non-5~10mg of content, 5~10mg of slow-released part tadalafil content, the mg of each preparation unit tadalafil content≤20.
Embodiment 9, clomipramine hydrochloride, Vardenafil hydrochloric acid oral instant membrane
100 g hydroxypropyl methyl celluloses after 60 DEG C of abundant swellings, are put into rapidly ice bath in 1000 m L redistilled waters
Stirring is spare to dissolving.Clomipramine hydrochloride raw material and Vardenafil hydrochloric acid raw material is taken to crushed 400 mesh sieve, it is spare.It will be above-mentioned
The ethanol solution of solution and drug is sufficiently stirred mixing, and adds in plasticizer, and corrigent etc. stirs and evenly mixs, and stands de-bubbled
Afterwards, film, 50 DEG C of dryings, demoulding are divided into 4 cm2(every hydrochloric clomipramine 20mg, hydrochloric acid are cut down the diaphragm of size
That non-20mg of ground).Half or 1 are taken during use.
Embodiment 10, clomipramine hydrochloride, sildenafil citrate Orally dissolving film
Hydroxypropyl methyl cellulose is taken, added in the clomipramine hydrochloride raw material and sildenafil citrate raw material powder of 400 mesh sieve
End, and plasticizer, lubricant and antioxidant etc. are added in, abundant mixing forms a film in 200 DEG C~220 DEG C hot melt extrudeds.It is divided into 4
cm2The diaphragm (every hydrochloric clomipramine 10mg, sildenafil citrate 50mg) of size.One is taken during use daily
It is secondary, each taking half or 1.
Embodiment 11, clomipramine hydrochloride, tadalafil oral instant membrane
100 g hydroxypropyl methyl celluloses after 60 DEG C of abundant swellings, are put into rapidly ice bath in 1000 m L redistilled waters
Stirring is spare to dissolving.Clomipramine hydrochloride raw material and Vardenafil hydrochloric acid raw material is taken to crushed 400 mesh sieve, it is spare.It will be above-mentioned
The absolute ethyl alcohol suspension of solution and drug is sufficiently stirred mixing, and add in plasticizer, and corrigent etc. stirs and evenly mixs, and stands degassing
After bubble, film, 50 DEG C of dryings, demoulding is divided into 4 cm2(every hydrochloric clomipramine 25mg, he reaches the diaphragm of size
That non-10mg).It is taken once a day during use, each taking half or 1.
Embodiment 12, clomipramine hydrochloride compound capsules
Clomipramine hydrochloride raw material and Na Fei class medicine materials are taken, crushed 200 mesh sieve, i.e. raw material particle size≤75 μm, is added in big
Abundant mixing in soya-bean oil, embedding is in the soft capsule shell made of gelatin, glycerine, water, antioxidant etc..To obtain the final product.
This product every hydrochloric clomipramine 5mg, Vardenafil hydrochloric acid 5mg, when use, take once a day, each taking
1~4.Or every hydrochloric clomipramine 5mg, sildenafil citrate 25mg, used time take once a day, each taking
1~4..Or every hydrochloric clomipramine 5mg, tadalafil 5mg, the used time takes once a day, each taking 1~4
Grain.
Embodiment 13, clomipramine hydrochloride, sildenafil citrate double-layer tablets
Clomipramine hydrochloride, sildenafil citrate fine powder are weighed respectively, 150 mesh sieve are crossed, respectively by following process operations：With fitting
Starch mixing is measured, it is appropriate to add starch slurry, mixing, and softwood is made, and crosses the wet grain of sieve series, dry, whole grain of being sieved.Take two kinds of particles
It is developed into double-layer tablets.Every hydrochloric clomipramine 12.5mg, sildenafil citrate 25mg during use once a day, take 1
~2.Or every hydrochloric clomipramine 6mg, sildenafil citrate 25mg, during use once a day, take 1~4.
Embodiment 14, clomipramine hydrochloride, Vardenafil hydrochloric acid control spansule
Take the fine powder mixing of ethyl cellulose and acrylic resin, after the dissolving of the ethyl alcohol of appropriate concentration, add in hydrochloric acid cut down ground that
Non- fine powder（Cross 200 mesh sieve）, softwood is made, is sieved, wet granular processed is dry, and B sustained release tablets are made in whole grain of being sieved, tabletting.
Clomipramine hydrochloride, Vardenafil hydrochloric acid fine powder are weighed respectively, 150 mesh sieve are crossed, respectively by following process operations：With
Appropriate amount of starch mixing, it is appropriate to add starch slurry, mixing, and softwood is made, and crosses the wet grain of sieve series, dry, whole grain of being sieved.Take two kinds
Grain is pressed into double-layer tablets.Obtain A+B quick-release double-layer tablets.
B sustained release tablets and A+B quick-release double-layer tablets are taken, the two is packed into same hard shell capsules.To obtain the final product
The hydrochloric clomipramine 12.5mg of every capsule immediate release section of this product, sildenafil citrate 25mg, slow-released part is containing Chinese holly
Sildena citrate 50mg, when use take within 2nd it is primary, 1~2 every time.Or the hydrochloric chlorine rice of every capsule immediate release section
Pa bright 6mg, sildenafil citrate 25mg, slow-released part 25mg containing sildenafil citrate, when use take within 2nd it is primary, often
Secondary 2~4.
Embodiment 15, clomipramine hydrochloride（A）, tadalafil（B）Control spansule
According to the processing step of embodiment 14, take part A that immediate-release granules are made, immediate-release granules are made in part B, are pressed into A+B speed
Double-layer tablets are released, while part A, B is taken to prepare sustained release tablets respectively and is pressed into A+B sustained-release double-layer tablets, the two is packed into same ebonite
In capsule.To obtain the final product.
Every immediate release section of this product hydrochloric clomipramine 12.5mg, tadalafil 5mg, the hydrochloric chlorine rice pa of slow-released part
Bright 12.5mg, tadalafil 10mg, when use take within 2nd it is primary, 1~2 every time.
Embodiment 16, clomipramine hydrochloride（A）, sildenafil citrate（B）Control spansule
It according to the processing step of embodiment 14, takes A that immediate-release granules are made, is pressed into A fast-release tablets, while take B that quick-release is respectively prepared
Particle and slow-releasing granules, and B double-layer tablets are pressed into, then A fast-release tablets and B double-layer tablets are fitted into same hard shell capsules.To obtain the final product.
The hydrochloric clomipramine 12.5mg of every capsule, quick-release sildenafil citrate 25mg, slow-released part is containing citric acid
Silaenafil 25mg, when use take within 2nd it is primary, 1~2 every time.
Embodiment 17, clomipramine hydrochloride（A）, sildenafil citrate（B）Control spansule
According to the processing step of embodiment 14, part A is taken respectively, immediate-release granules and slow-releasing granules are made, be pressed into A double-layer tablets,
It takes B that immediate-release granules and slow-releasing granules are respectively prepared, and be developed into B double-layer tablets simultaneously, is then packed into A double-layer tablets and B double-layer tablets
In same hard shell capsules.To obtain the final product.Every capsule clomipramine hydrochloride containing quick-release 12.5mg is sustained clomipramine hydrochloride 12.5mg, contains
Quick-release sildenafil citrate 25mg, slow-released part 25mg containing sildenafil citrate, when use take within 2nd it is primary, every time 1
~2.
Embodiment 18, clomipramine hydrochloride（A）, Vardenafil hydrochloric acid（B）Control spansule
In centrifugal coating granulator, using PVP alcoholic solutions as binder, clomipramine hydrochloride and salt are wrapped in the heart in blank pill
Sour Vardenafil active drug nitride layer, 60 DEG C of dryings, obtains medicament pellet；In centrifugal coating granulator, wrapped on medicament pellet
Upper sustained-release coating layer coating solution controls the dosage of coating solution according to rate of release, dry to get pharmaceutical pellet through 40-50 DEG C.By rule
Capsule is quantitatively packed into get clomipramine hydrochloride, Vardenafil hydrochloric acid compound control spansule.This control spansule 3~24 is small
When interior release clomipramine hydrochloride 15mg, Vardenafil hydrochloric acid 10mg；24~48 hours release clomipramine hydrochloride 15mg, hydrochloric acid
Vardenafil 5mg.This product is taken every other day, 1 tablet each time.
Embodiment 19, clomipramine hydrochloride（A）, tadalafil（B）Control spansule
In centrifugal coating granulator, using PVP alcoholic solutions as binder, clomipramine hydrochloride activity is wrapped in the heart in blank pill
Medicine layer, 60 DEG C of dryings, obtains medicament pellet；In centrifugal coating granulator, sustained-release coating layer coating is wrapped on medicament pellet
Liquid controls the dosage of coating solution according to rate of release, dry to get clomipramine hydrochloride pharmaceutical pellet through 40-50 DEG C.
Tadalafil pharmaceutical pellet is made by above-mentioned technique.
Two kinds of pharmaceutical pellets are packed into capsule to obtain the final product.
This control spansule discharges clomipramine hydrochloride 25mg, tadalafil 10mg in 3~24 hours；It releases within 24~48 hours
Put clomipramine hydrochloride 15mg, Vardenafil hydrochloric acid 5mg.This product is taken every other day, 1 tablet each time.
Embodiment 20, clomipramine hydrochloride（A）, tadalafil（B）Sustained release tablets
Clomipramine hydrochloride and tadalafil fine powder are crossed into 400 mesh sieve, mixed in proportion, by Cabosil M5（A kind of titanium dioxide
Silica hydrogel）It is added in the stearyl alcohol of fusing, adds the part fine powder of above-listed two kinds of drugs, be sufficiently stirred, when nearly solidifying, mistake
Sieve series grain is pressed into the piece heart (slow-released part).The remaining fine powder of above-listed two kinds of drugs finally is wrapped in piece heart surface by coating method to make
For immediate release section.Tablet is made.
Every capsule clomipramine hydrochloride containing quick-release 20mg is sustained clomipramine hydrochloride 10mg, tadalafil containing quick-release
10mg, slow-released part tadalafil 5mg, when use take within 2nd it is primary, 1 tablet each time.
Embodiment 21, clomipramine hydrochloride（A）, Vardenafil hydrochloric acid（B）Sustained release tablets
By part clomipramine hydrochloride micro mist, Vardenafil hydrochloric acid micro mist and lactose, microcrystalline cellulose and crosslinked polyethylene pyrroles
Alkanone mixing is that adhesive is pelletized with polyvinylpyrrolidone and lauryl sodium sulfate mixed aqueous solution.Stiffened fatty acid magnesium and
Remaining crosslinked polyvinylpyrrolidone, mixing are pressed into the piece heart.
By remainder clomipramine hydrochloride micro mist, Vardenafil hydrochloric acid, microcrystalline cellulose with low concentration hydroxypropyl methyl
Cellulose aqueous solution is pelletized for adhesive, stiffened fatty acid magnesium after drying, mixing.The piece heart is pressed together with pressed coated layer particle
Piece.To obtain the final product.
Every capsule clomipramine hydrochloride containing quick-release 10mg, be sustained clomipramine hydrochloride 10mg, hydrochloric acid containing quick-release cut down ground that
Non- 10mg, slow-released part tadalafil 5mg, when use take within 2nd it is primary, 1~2 every time.
Embodiment 22, below by way of experiment directly observation compound clomipramine to the shadow of isolated rat vas deferens contraction function
It rings, should have the function of diastole isolated rat vas deferens researches show that compound clomipramine, compound clomipramine has been prompted to have and has been prolonged
The pharmacological basis of slow male rat ejaculation.
1. materials and methods
1.1 materials and instrument
1.1.1 Experimental Animals Male adult Wistar rat（250g-350g）,
1.1.2 drug and main agents
（1）Sildenafil citrate, clomipramine hydrochloride；Wherein：
Sildenafil citrate concentration range：10-7mol/L~10-4 mol/L；
1 concentration range of compound clomipramine：（1mol sildenafil citrate+1mol clomipramine hydrochlorides）*10-7/L~（1mol
Sildenafil citrate+1mol clomipramine hydrochlorides）*10-4/L;
1 concentration range of compound clomipramine：（1mol sildenafil citrate+2mol clomipramine hydrochlorides）*10-7/L~（1mol
Sildenafil citrate+2mol clomipramine hydrochlorides）*10-4/L;
（2）Krebs-Henseint liquid ingredient (mmol L-1):NaCl 118, KCl 5.6, CaCl22.5, Mg SO4
1.2, KH2PO4 0.9, Na HCO325, Glucose 11；
（3）Other reagents are pure for domestic analysis.
1.1.3 instrument
Desk-top self-balancing recorder, bis- physiographs of LMS-2B, Muscle tensility energy converter, thermostatic water-circulator bath pot, journey
Control egersimeter.
1.2 method
1.2.1 the influence of isolated rat vas deferens smooth muscle tension
It is prepared by sample：Adult male rats cervical dislocation is put to death, and is taken vas deferens rapidly, is placed in and fills Krebs-
In the culture dish of Henseint liquid, it is passed through mixed gas（95%O2, 5%CO2）, sample is divided into two from centre, by vas deferens
It is fixed in specimen plate, immerses and fill in the 10ml organ baths of Krebs-Henseint liquid, be passed through mixed gas, 37 DEG C
Constant temperature water bath.Muscle tensility energy converter is connected, recording sample by desk-top balance recorder relaxes contracting
Variation.Preload 1g power balances 1h, it is primary to replace nutrient solution within during which every 15 minutes.Sample is with 80 mmol L1KCl stimulations are shunk.Electrical field stimulation is generated using YC-2 type programmed electrical stimulations device, and sample is placed in parallel opposite platinum
Between electrode.Stimulation voltage 40V, 0.05Hz, 3ms.The accumulation administration of 1/2lg molar concentrations, records administration or electro photoluminescence every time
The diastole degree of sample afterwards.All stretching reactions（Relaxation）It is expressed as being equivalent to and inhibits 80mmol L- 1KCl or electricity
Stimulation causes the percentage of contraction.
2. result
The effect of rat spermatic duct that 2.1 compound clomipramines shrink KCl stimulations
With 80 mmol L- 1The rat spermatic duct sample that shrinks of high concentration KCl inductions on, it is sildenafil citrate, multiple
Square clomipramine 1 causes the diastole effect of vas deferens, compound chlorine rice pa with 2 equal cocoa concentration dependent of compound clomipramine
Bright 1, compound clomipramine 2 has significant difference compared with sildenafil citrate（p<0.05）.
Note：* compound clomipramine 1 is meant（Relaxation2）, compound clomipramine 2（Relaxation3）With western ground that
It is non-（Relaxation1）Compare, there is significant difference（p<0.05）
The effect of rat spermatic duct that 2.2 compound clomipramines shrink electro photoluminescence
With 0.05Hz, 3ms, on the rat spermatic duct sample that 40V electro photoluminescence induction is shunk, sildenafil citrate, compound
Clomipramine 1 causes the diastole effect of vas deferens, compound clomipramine with 2 equal cocoa concentration dependent of compound clomipramine
1st, compound clomipramine 2 has significant difference compared with sildenafil citrate（p<0.05）.
Note：* compound clomipramine 1 is meant（Relaxation2）, compound clomipramine 2（Relaxation3）With western ground that
It is non-（Relaxation1）Compare, there is significant difference（p<0.05）.
Claims (10)
1. a kind of pharmaceutical composition, it is characterised in that：Its effective ingredient is mainly made of clomipramine hydrochloride and Na Fei class drugs.
2. pharmaceutical composition as described in claim 1, it is characterised in that：Both in effective ingredient, clomipramine hydrochloride accounts for
Mass ratio is 0.1：1~10.
3. pharmaceutical composition as claimed in claim 1 or 2, it is characterised in that：That non-class drug for Vardenafil hydrochloric acid or
Sildenafil citrate or tadalafil.
4. a kind of drug delivery system of pharmaceutical composition as described in claims 1 or 2 or 3, it is characterised in that：The drug is passed
System is sent as pharmaceutically acceptable preparation, preferably Orally dissolving film either soft capsule or control sustained release preparation.
5. drug delivery system as claimed in claim 4, it is characterised in that：In the Orally dissolving film, hydrochloric acid chlorine rice
The bright raw material of pa and Na Fei class raw materials crushed 400 mesh sieve, i.e. raw material particle size≤38 μm, with hydroxypropyl methyl cellulose or low take
For hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, hyaluronic acid, Polyvinylcaprolactame-polyvinyl acetate-poly- second two
Alcohol copolymer, polyethylene oxide, cellulose acetate, polyvinylpyrrolidone, polymethylacrylic acid-methyl acrylate-methyl
Acrylic acid, hypromellose phthalate, ethyl cellulose, cellulose acetate-butyrate, secondary amine epoxy resin, methyl-prop
One or both of olefin(e) acid trimethylammonium ethyl ester methacrylate copolymer ingredient, prepares membrane carrier jointly.
6. drug delivery system as claimed in claim 4, it is characterised in that：Clomipramine hydrochloride raw material and Na Fei classes drug are former
Material crushed 200 mesh sieve, i.e. raw material particle size≤75 μm, filling in being main using gelatin, G ＆ W using vegetable oil as dispersion
Material is made in soft capsule, and soft capsule is made.
7. such as the drug delivery system any one of claim 4-6, it is characterised in that：Contain in each preparation unit
Clomipramine hydrochloride 5mg~25mg, 25~50mg of silaenafil；Or hydrochloric clomipramine 5mg~25mg, tadalafil
5mg~10mg；Or containing sour clomipramine 5mg~25mg, Vardenafil hydrochloric acid 5mg~10mg.
8. drug delivery system as claimed in claim 4, it is characterised in that：Control sustained release preparation be with clomipramine hydrochloride A with
Quick-release that non-class B raw material is either mixed respectively delivering body and/or by clomipramine hydrochloride A and that non-class B respectively or
The sustained release delivery body composition being mixed；150 μm ~ 38 μm of the particle size range of clomipramine hydrochloride, that non-class raw material；
Including：（1）Immediate-release granules are made in A, and immediate-release granules are made in B, are then pressed into double-layer tablets；Alternatively, take A that quick-release is made
Grain, part B are made immediate-release granules, are pressed into A+B quick-release double-layer tablets, while part B is taken to be prepared into sustained release tablets, the two are packed into same
One hard shell capsules；Alternatively, taking part A that immediate-release granules are made, immediate-release granules are made in part B, are pressed into A+B quick-release double-layer tablets, simultaneously
Part A, B is taken to prepare sustained release tablets respectively and is pressed into A+B sustained-release double-layer tablets, the two is fitted into same hard shell capsules；Or take A systems
Into immediate-release granules, A fast-release tablets are pressed into, while take B that immediate-release granules and slow-releasing granules are respectively prepared, and are pressed into B double-layer tablets, so
A fast-release tablets and B double-layer tablets are fitted into same hard shell capsules afterwards；Alternatively, taking A that immediate-release granules and slow-releasing granules are respectively prepared, suppress
It into A double-layer tablets, while takes B that immediate-release granules and slow-releasing granules are respectively prepared, and is developed into B double-layer tablets, then by A double-layer tablets and B
Double-layer tablets are fitted into same hard shell capsules；
（2）A, control sustained release pellet is respectively prepared in the control spansule or A, B that B is mixed, then mixing dress hard shell capsules；
（3）B sustained release tablets are prepared with part B, using B sustained release tablets as the piece heart, A and part B are taken to mix, coating material or compacting packet is made
Clothing layer particle, is coated B sustained release tablets, and the tablet or piece heart is tabletted together with pressed coated layer particle is made；Or
Person is mixed with AB sustained release tablets with part A and part B, using AB sustained release tablets as the piece heart, part A and part B is taken to mix, packet is made
Clothing material or pressed coated layer particle, are coated AB sustained release tablets, tablet are made or by the piece heart and pressed coated layer particle one
It rises tabletted.
9. drug delivery system as claimed in claim 8, it is characterised in that：Its immediate release section hydrochloric acid chlorine rice of each preparation unit
The bright content 5mg~25mg of pa, 15 mg of slow-released part clomipramine hydrochloride content~50mg, each preparation unit hydrochloric acid chlorine rice pa
The mg of bright content≤75；Each preparation unit that non-25~50mg of content of its immediate release section, slow-released part sildenafil citrate contain
Measure 25~50mg, the mg of each preparation unit sildenafil citrate content≤100；Alternatively, immediate release section Vardenafil hydrochloric acid contains
Measure 5~10mg, 5~10mg of slow-released part Vardenafil hydrochloric acid content, each preparation unit Vardenafil hydrochloric acid content≤20
mg；Alternatively, immediate release section tadalafil 5~10mg of content, slow-released part 5~10mg of tadalafil content, each preparation unit
The mg of tadalafil content≤20.
10. pharmaceutical composition described in claims 1 or 2 or 3 is preparing for extending the use in male's sexual life time drug
On the way.
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| CN201810010260.5A CN108126203A (en) | 2018-01-05 | 2018-01-05 | A kind of pharmaceutical composition and its drug delivery system and purposes |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007000764A2 (en) * | 2005-06-27 | 2007-01-04 | Daniel Drai | Compositions and methods for enhancement of sexual function |
| KR20150105496A (en) * | 2014-03-06 | 2015-09-17 | (주) 에프엔지리서치 | Oral pharmaceutical preparations comprising dapoxetine or chlromipramine hydrochloride and pde 5 inhibitors in separated form |
| CN105899193A (en) * | 2013-12-31 | 2016-08-24 | 西梯茜生命工学股份有限公司 | Hot melt fragmentation extruder and process |
-
2018
- 2018-01-05 CN CN201810010260.5A patent/CN108126203A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007000764A2 (en) * | 2005-06-27 | 2007-01-04 | Daniel Drai | Compositions and methods for enhancement of sexual function |
| CN105899193A (en) * | 2013-12-31 | 2016-08-24 | 西梯茜生命工学股份有限公司 | Hot melt fragmentation extruder and process |
| KR20150105496A (en) * | 2014-03-06 | 2015-09-17 | (주) 에프엔지리서치 | Oral pharmaceutical preparations comprising dapoxetine or chlromipramine hydrochloride and pde 5 inhibitors in separated form |
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