CN104352436A - Nitroglycerin in-situ forming gel spray and preparing method thereof - Google Patents
Nitroglycerin in-situ forming gel spray and preparing method thereof Download PDFInfo
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- CN104352436A CN104352436A CN201410526716.5A CN201410526716A CN104352436A CN 104352436 A CN104352436 A CN 104352436A CN 201410526716 A CN201410526716 A CN 201410526716A CN 104352436 A CN104352436 A CN 104352436A
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Abstract
The invention belongs to the field of pharmaceutic preparations and relates to a drug for treating erectile dysfunction and a preparing method thereof. The drug is used for promoting more rapid, lasting and efficient erection with small toxic side effect. A solution of a spray comprises nitroglycerin, a surfactant, a cosurfactant, a thermo-sensitive polymer material, a stabilizer and a water phase and specifically comprises the following ingredients in percentage by weight: 0.5-5% of nitroglycerin, 1-10% of Twain, 1-10% of ethanol, 5-30% of thermo-sensitive polymer material, 1-8% of hydroxypropyl methyl cellulose and the rest of water. The preparing method of the nitroglycerin spray comprises the following steps: (1) weighing the thermo-sensitive polymer material and dissolving in a proper quantity of water; (2), weighing the nitroglycerin, the ethanol and the Twain and uniformly mixing; (3) uniformly mixing two parts, fully agitating, adding the stabilizer and adding water to a certain volume.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to a kind of medicine for the treatment erection disturbance rapider, lasting, efficient, toxic and side effects is little that erects and preparation method thereof, particularly nitroglycerin shaped in situ gel spray and preparation method thereof.
Technical background
Male erectile dysfunction (be called for short ED) refers to that male is when there being libido, and penis anorthosis maybe can erect but not hard, can not Progressive symmetric erythrokeratodermia movable and cause dyspareunia.Erectile dysfunction is the general problem of male, and the adult male of nearly 10% there will be erection problem according to statistics, and this handicapped coverage sharply increases along with the increase at age.The reason of erection problem or psychogenic, organic, iatrogenic or prohormone are because causing.It is not considered to be easy to the medical symptom for the treatment of under normal conditions, to a great extent this be caused by mental status or at least aggravate owing to losing the confidence after initial experience, described initial experience may have fatigue or excessive drinking to cause.But the psychological infringement produced for patient is quite serious, will destroy normal harmonious life and fertilization process in many cases.May occur in some old patients based on organic dysfunction, cause, such as arteriosclerosis, hypertension etc. due to their blood vessel, spongy body or nervous system disease.The dysfunction that iatrogenic factor causes then mainly appears at after medication or after some M-C treatment meanss, and such as antihypertensive and hypoglycemia side effects of pharmaceutical drugs also can cause erection problem.Prohormone because of the erection problem caused be the change of change due to testosterone or other hormones and chemicals.
The therapeutic scheme of erection problem depends on the above-mentioned reason caused, and therapeutic scheme is a lot, such as psychotherapy, vascular surgery, Surgical revision or conventional pharmacotherapy.Conventional pharmacotherapy is as injected in oral drugs, topical and urethra or in cavernous sinus.The reason of erection disturbance determines the selection of therapy approach, the kind of medicine and route of administration etc.Sufferers themselves and spouse thereof may be made to have side effects by the administration of urethral routes.Because the medicine retention of a part is in urethra and pass to spouse in coitus; The self-injection approach of administration in cavernous sinus also has its disadvantageous one side, and patient lacks spontaneity and easily produces unhappy, and the compliance of patient is poor.Although oral drugs facilitate and are the good therapy approach of a kind of patient's compliance, the bioavailability of this mode has certain limitation, and physiological reaction speed is slower.Such as oral sldenafil sheet, its Biomass availability is 40%.Talk endlessly after oral the time T of peak plasma concentration
max, be 30-120 minute (average out to 60 minutes) in the fasted state, but the diet of high fat can make T
maxincrease by 60 minutes, reach peak concentration less 29%.From clinical viewpoint, the curative effect that the effect that sldenafil sheet produces produces along with the change of dietary structure changes.Percutaneous dosing mode is widely used in some specific dysfunction of systematic treating.A large amount of assay optimization percutaneous dosing is in the method for penis, and this method to make sexual intercourse success really, therefore result in the development of various transdermal delivery system.
Nitroglycerin is antianginal old medicine, clinical practice has the history of more than 100 year, it rapid-action but effect maintain short, nitrate esters smooth muscle cell can with nitrate receptors bind, and be reduced into NO or-SNO(nitrous sulfenyl by the sulfydryl of nitrate receptor).In addition, the NO of release can also suppress hematoblastic gathering and adhesion, is conducive to the treatment of coronary heart disease.
Along with to NO more and more deep understanding of the mechanism of action in circulation, immunity and nervous system, the application of NO and NO associated medication therapies is more and more extensive.Relation table between nitric oxide and sexual function is present, and when being subject to sexual stimulus, the local of sexual organ can generate a large amount of nitric oxide, intracellular cGMP can be made to raise, cause erection thus.
Progress and the Clinical practice of domestic and international relevant nitroglycerin treatment erection disturbance are comparatively extensive.The patent of invention that Futura Medical Ltd. of Britain applies in China " is used for the treatment of the preparation of erectile dysfunction " (the ZL patent No. 99803716.8).Said composition is primarily of the water composition of the nitroglycerin (10%, in lactose) of 10% weight, the lanoline of 44% weight, the paraffin wax white of 21% weight and 25% weight.Said preparation uses lipophilic lanoline as the substrate of nitroglycerin, and its time reached needed for erection is significantly changed, and incubation period is 1-2 hour.The speed that these lipophilic substrate not only cause nitroglycerin to discharge to penile tissue slowly, but also make oiliness residue stay on penis, like this, the nitroglycerin contained in this oiliness residue is not easy to discharge from vagina, is transferred to companion on the contrary by vaginal mucosa.Another shortcoming of said preparation is used to be, when using these preparations on penis, have strong burning sensation and produce; And need when using constantly to smear with hands, cause medicine from other site absorption, produce untoward reaction.
Patent of invention that International Medical Innovations, Inc. of the U.S. applies in China " the water base medicinal external emulsifiable paste and its preparation method and application containing nitroglycerin " (the ZL patent No. 96192273.7), this medicinal external emulsifiable paste is by the nitroglycerin of 0.1-3 % by weight, the penetration enhancer of 5-24% % by weight, the water of 60-90 % by weight, the thickening agent of 0.5-3 % by weight and the emulsifying agent of 0.4-2% % by weight formed.Point out the poor stability of said preparation in patent 200410014738.X, reason is that the water containing 60-90 % by weight in preparation will make nitroglycerin be hydrolyzed.Nitroglycerin is generally all kept in dehydrated alcohol.The existence of dehydrated alcohol causes the less stable of preparation.
Summary of the invention
In order to solve above-mentioned technical problem, first object of the present invention is to provide stable nitroglycerin shaped in situ gel spray, solve the impact of dehydrated alcohol on preparation stability well, comprise being uniformly distributed of gel in nitroglycerin chemical stability and preparation prescription, have easy to use, can Direct spraying administration, form medicine film immediately after contact skin, effectively prevent fluid loss, have more the advantages such as erection effect is rapid, lasting, toxic and side effects is little.Second object of the present invention is to provide the preparation method of nitroglycerin microemulsion shaped in situ gel spray.
In order to realize first above-mentioned object, present invention employs following technical scheme:
The spray of nitroglycerin shaped in situ, the solution of this spray comprises nitroglycerin, surfactant, cosurfactant, temperature sensing polymer material, stabilizing agent and aqueous phase composition, composition comprises: by weight percentage, nitroglycerin 0.5 ~ 5%, tween 1 ~ 10 %, ethanol 1 ~ 10 %, temperature sensing polymer material 5 ~ 30 %, hypromellose 1 ~ 8%, surplus is water.
As preferably, by weight percentage, nitroglycerin 1 ~ 4%, tween 2 ~ 8 %, ethanol 2 ~ 8%, temperature sensing polymer material 10 ~ 25%, hypromellose 2-7%, surplus is water.
As preferred again, by weight percentage, nitroglycerin 2 ~ 3%, tween 3 ~ 5 %, ethanol 3 ~ 5%, temperature sensing polymer material 15 ~ 20%, hypromellose 4 ~ 6%, surplus is water.
As preferably, above-mentioned tween selects one or more in Tween-60, tween 80.
One or more as preferably, in above-mentioned temperature sensing polymer material selection hyaluronate sodium, poloxamer.As preferred again, by one or more of temperature sensing polymer material selection poloxamer188 and PLURONICS F87.
In order to realize second above-mentioned object, present invention employs following technical scheme:
Prepare a method for above-mentioned Nitrolingual, the preparation method of the solution of this Nitrolingual comprises the following steps:
(1) take temperature sensing polymer material, be dissolved in suitable quantity of water;
(2) nitroglycerin, ethanol and tween is taken, mix homogeneously;
(3) by two parts mix homogeneously, fully stir, add stabilizing agent, add water to 100ml.
The present invention, owing to have employed above technical scheme, has following advantage and effect:
1) nitroglycerin is made shaped in situ spray, sprayable administration, convenient and swift, coating evenly, consumption is adjustable.Original position film forming can be understood after contact skin, compared with common spray, can prolong drug in the delay of target site, extend drug effect, simultaneously can not pollution clothes or loss, ensure that dosage is accurate.
2) application of the present invention in treatment erection problem problem is much better than the additive method proposed so far.The composition of said preparation is only used for the finished product of people containing approved, inapplicablely not yet permit the penetrating agent such as the dimethyl sulfoxine used in this type of purposes.Within a short period of time of the present invention, (5-10 minute) worked, and effect lasts 30 minutes to 2 hours.
3) nitroglycerin has the effect of blood vessel dilating, common oil base or water base emulsifiable paste, is with fingerstall or rubber gloves, is prepared into shaped in situ spray when need embrocate, and can reduce other positions of health or infect other people risk.On the other hand, the nitroglycerin in the present invention absorbs fast, and therefore, if there is active component to be transferred to sex partner, its amount is also less, and the side reaction caused is lower.
4) nitroglycerin routine preservation is in dehydrated alcohol, and the existence of dehydrated alcohol have impact on the swelling of thermo-responsive hydro gel in shaped in situ gel spray, makes it be difficult to form molecule colloidal sol, long-term place after thermo-responsive hydro gel material easily separate out.The present invention is found by large quantity research, adds the dissolving that a certain amount of Tween-60 or tween 80 well can increase thermo-responsive hydro gel in position in shaping gel spray, prevents from separating out; Nitroglycerin stability in aqueous can be increased again on the other hand.
Detailed description of the invention
With specific embodiment, technical scheme of the present invention is described further below, but protection scope of the present invention is not limited thereto.
Embodiment 1
Nitroglycerin 0.5g
Tween 80 1g
Ethanol 10g
Poloxamer188 30g
Hypromellose 1g
Water adds water to 100ml
Preparation technology:
(1) take temperature sensing polymer material, be dissolved in suitable quantity of water;
(2) nitroglycerin, ethanol and tween 80 is taken, mix homogeneously;
(3) by two parts mix homogeneously, fully stir, add stabilizing agent, add water to 100ml, accurately put in spray bottle and namely obtain nitroglycerin shaped in situ gel spray.
Embodiment 2
Nitroglycerin 5g
Tween-60 10g
Ethanol 1g
PLURONICS F87 5g
Hypromellose 8g
Water adds water to 100ml
Preparation technology:
(1) take temperature sensing polymer material, be dissolved in suitable quantity of water;
(2) nitroglycerin, ethanol and Tween-60 is taken, mix homogeneously;
(3) by two parts mix homogeneously, fully stir, add stabilizing agent, add water to 100ml, accurately put in spray bottle and namely obtain nitroglycerin shaped in situ gel spray.
Embodiment 3
Nitroglycerin 1g
Tween 80 2g
Ethanol 2g
Poloxamer188 10g
Hypromellose 2g
Water adds water to 100ml
Preparation technology:
(1) take temperature sensing polymer material, be dissolved in suitable quantity of water;
(2) nitroglycerin, ethanol and tween 80 is taken, mix homogeneously;
(3) by two parts mix homogeneously, fully stir, add stabilizing agent, add water to 100ml, accurately put in spray bottle and namely obtain nitroglycerin shaped in situ gel spray.
Embodiment 4
Nitroglycerin 4g
Tween-60 8g
Ethanol 8g
PLURONICS F87 25g
Hypromellose 7g
Water adds water to 100ml
Preparation technology:
(1) take temperature sensing polymer material, be dissolved in suitable quantity of water;
(2) nitroglycerin, ethanol and Tween-60 is taken, mix homogeneously;
(3) by two parts mix homogeneously, fully stir, add stabilizing agent, add water to 100ml, accurately put in spray bottle and namely obtain nitroglycerin shaped in situ gel spray.
Embodiment 5
Nitroglycerin 2g
Tween 80 5g
Ethanol 4g
Poloxamer188 20g
Hypromellose 5g
Water adds water to 100ml
Preparation technology:
(1) take temperature sensing polymer material, be dissolved in suitable quantity of water;
(2) nitroglycerin, ethanol and tween 80 is taken, mix homogeneously;
(3) by two parts mix homogeneously, fully stir, add stabilizing agent, add water to 100ml, accurately put in spray bottle and namely obtain nitroglycerin shaped in situ gel spray.
Claims (7)
1. a nitroglycerin shaped in situ gel spray, be made up of nitroglycerin, surfactant, cosurfactant, temperature sensing polymer material, stabilizing agent and aqueous phase, it is characterized in that component comprises: by weight percentage, nitroglycerin 0.5 ~ 5%, tween 1 ~ 10 %, ethanol 1 ~ 10 %, temperature sensing polymer material 5 ~ 30 %, hypromellose 1 ~ 8%, surplus is water.
2. spray according to claim 1, is characterized in that component comprises: by weight percentage, and nitroglycerin 1 ~ 4%, tween 2 ~ 8 %, ethanol 2 ~ 8%, temperature sensing polymer material 10 ~ 25%, hypromellose 2 ~ 7%, surplus is water.
3. spray according to claim 2, is characterized in that component comprises: nitroglycerin 2 ~ 3%, tween 3 ~ 5 %, ethanol 3 ~ 5%, temperature sensing polymer material 15 ~ 20%, hypromellose 4 ~ 6%, surplus is water.
4. spray according to claim 1, is characterized in that one or more that tween selects in Tween-60, tween 80.
5. spray according to claim 1, is characterized in that one or more in temperature sensing polymer material selection hyaluronate sodium, poloxamer.
6. the poloxamer described in claim 4, is characterized in that poloxamer selects one or more of poloxamer188 and PLURONICS F87.
7., according to the preparation method of the arbitrary described a kind of nitroglycerin shaped in situ gel spray of claim 1-3, it is characterized in that the method is: take temperature sensing polymer material, be dissolved in suitable quantity of water; Take nitroglycerin, ethanol and tween, mix homogeneously; By two parts mix homogeneously, fully stir, add stabilizing agent, add water to 100ml, accurately put in spray bottle and namely obtain nitroglycerin shaped in situ gel spray.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410526716.5A CN104352436A (en) | 2014-10-09 | 2014-10-09 | Nitroglycerin in-situ forming gel spray and preparing method thereof |
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| CN201410526716.5A CN104352436A (en) | 2014-10-09 | 2014-10-09 | Nitroglycerin in-situ forming gel spray and preparing method thereof |
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| CN104352436A true CN104352436A (en) | 2015-02-18 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1307472A (en) * | 1998-05-18 | 2001-08-08 | 巴克·诺顿药物有限公司 | Compositions comprising organic mono-or dinitrate for treating impotence |
| CN1491647A (en) * | 2002-10-22 | 2004-04-28 | 刘小兵 | Composition for percutaneous treating impotence and female sexual cold and preventing sextual disease |
| CN102204887A (en) * | 2011-06-09 | 2011-10-05 | 浙江浙北药业有限公司 | In-situ formed acyclovir spraying agent and preparation method thereof |
-
2014
- 2014-10-09 CN CN201410526716.5A patent/CN104352436A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1307472A (en) * | 1998-05-18 | 2001-08-08 | 巴克·诺顿药物有限公司 | Compositions comprising organic mono-or dinitrate for treating impotence |
| CN1491647A (en) * | 2002-10-22 | 2004-04-28 | 刘小兵 | Composition for percutaneous treating impotence and female sexual cold and preventing sextual disease |
| CN102204887A (en) * | 2011-06-09 | 2011-10-05 | 浙江浙北药业有限公司 | In-situ formed acyclovir spraying agent and preparation method thereof |
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Application publication date: 20150218 |