CN1814253A - Heat-sensitive gel preparation and preparing method - Google Patents
Heat-sensitive gel preparation and preparing method Download PDFInfo
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Abstract
The invention relates to temperature sensing gel preparation and its method of preparation. The preparation is made up of vegetable essential oil, boneol or mentha camphor alcohol solution, poloxamer 407 solution, and antiseptic. It is sensitive to temperature. It is flexible liquid at normal temperature. While near to 28-33 centigrade degree it forms gel. It can be used in human or animal cavity channel mucous membrane, such as oral cavity, nasal cavity, rectum, and vagina.
Description
Technical field
The present invention relates to a kind of heat-sensitive gel preparation, being specifically related to a kind of is active component with the plant volatile oil, contain the alcoholic solution of Mentholum or Borneolum Syntheticum, the Pharmaceutical composition of poloxamer 407, said composition has heat-sensitive gel, can use human body or animal tracts such as oral cavity, nasal cavity, rectum or vagina.The invention still further relates to the preparation method of this heat-sensitive gel preparation.
Background technology
Freezing pointes such as Oleum Curcumae, Fructus Cnidii oil, Oleum menthae, patchouli oil, perilla oil, Oleum Anisi Stellati, Oleum Caryophylli, Oleum Cinnamomi, litsea cubeba oil, Semen Juglandis distilling oil are not less than 15 ℃ plant volatile oil and can be used for treating body cavities diseases such as oral cavity, nasal cavity, rectum or vagina in Chinese medicines, at present widely used is that the non-endo-medicine dosage form of active pharmaceutical ingredient is generally oil solution, ointment, cream with the plant volatile oil, conventional dosage forms when reality is used, exist greasy by force, the defective of bioaffinity difference.
Gel is a kind of dosage form that is applicable to the mucosa medication, the semifluid preparation that is mixed and made into by active medicine, with its adjuvant that can form the macromolecular network system, with mucosa good coupling and hydration are arranged, but long period and site of action tight adhesion, better biocompatibility is arranged, no greasy feeling helps drug release.The holdup time of gel in mucosa is relevant with its viscosity, and viscosity is high more, be detained of a specified duration more, but the gel viscosity height is just inconvenient during use, is difficult to extrude in container, also is not easy to be evenly distributed at affected part.Thermal sensitive gel is a kind of liquid at room temperature in a flowable, undergoes phase transition under the temperature conditions influence near body temperature, and solution viscosity sharply increases the preparation that changes gel into, and thermal sensitive gel can overcome the use defective of ordinary gel agent.This dosage form also is specially adapted to the drug administration of oral cavity and nasal cavity, can form gel after the drug solution that spray bottle sprays arrives site of action.
Poloxamer 407 (being also referred to as the general Luo Ning F-127 of stream) is a kind of adjuvant of preparation gel for the block copolymer of polyoxyethylene and polyoxypropylene composition.The aqueous solution of poloxamer 407 has certain heat-sensitive gel character, but this character is desirable not enough, according to record, poloxamer 407 is when its best temperature-sensitive concentration 25%, when temperature during from 15 ℃ to 20 ℃, viscosity from＜1000/mPa is prominent more to 214000/mPa, but from 20 ℃ to 35 ℃, viscosity is increased to 258000/mPa from 214000/mPa, only increased by 20% (medicinal biodegradation macromolecular material, Guo Shenglong chief editor, Chemical Industry Press, 2004,78 pages).Chinese patent application CN1593386A and CN1377706A all disclose a kind of poloxamer 407 and method of carrying out proportioning than the poloxamer 188 of small-molecular weight of adopting, and have obtained to have the heat-sensitive gel prescription near the phase transition temperature of body temperature.But owing to use two kinds of poloxamers simultaneously, the toatl proportion of poloxamer material is higher in causing writing out a prescription, and the total concentration of effective poloxamer reaches 30%-37% and 30%-50% respectively in the prescription that Chinese patent application CN1593386A and CN1377706A disclose.So corresponding material consumption increases, also may make heat-sensitive gel before undergoing phase transition solution viscosity just than higher, inconvenience when causing using.
The thermal sensitive gel that 407 preparations of the relevant poloxamer of use separately have near the phase transition temperature of body temperature does not appear in the newspapers as yet.
Summary of the invention
The object of the invention is to provide a kind of heat-sensitive gel preparation, and said preparation is active pharmaceutical ingredient with the plant volatile oil, is adjuvant with the alcoholic solution of Mentholum or Borneolum Syntheticum, poloxamer 407 etc., has the phase transition temperature near body temperature.Be low viscous flowable liquids shape under the room temperature, be subjected to temperature influence after being applied to mucosal sites, undergo phase transition, solution viscosity significantly increases, and changes high viscosity into, immobilising gel, and this phase transformation is reversible.
Another object of the present invention is to provide the preparation method of this thermosensitive type gel preparation.
The present invention discloses, and can improve the temperature-sensitive character of poloxamer 407 solution after the alcoholic solution combination of the plant volatile oil of specific concentrations and Borneolum Syntheticum or Mentholum, has the phase transition temperature near body temperature, can make to be applied to human body or mucous membrane of animal thermal sensitive gel.
By weight, heat-sensitive gel preparation of the present invention is composed as follows:
Plant volatile oil 1%～4%
Borneolum Syntheticum or Mentholum 1%～4%
Ethanol 8%～12%
Poloxamer 407 solution 81%～88%
Antiseptic 0%～0.07%
In the above-mentioned prescription, plant volatile oil is that freezing point is not less than 15 ℃, the normally used volatile oil that from plant, extracts in the Chinese medicine, as Oleum Curcumae, Oleum Fructus Bruceae, Fructus Cnidii oil, Oleum Folium Artemisiae Argyi, Radix Angelicae Sinensis oil, Rhizoma Chuanxiong oil, Myrrha, Oleum Anisi Stellati, Oleum Ocimi Gratissimi, Oleum Cinnamomi, Oleum Camelliae, Oleum Eucalypti, Oleum menthae, patchouli oil, fruit of cubeb litsea tree oil, perilla oil, Semen Juglandis distilling oil, Herba Rosmarini Officinalis volatile oil, Radix Angelicae Dahuricae oil, Herba Schizonepetae oil, Fructus Forsythiae oil, Pericarpium Citri Reticulatae wet goods, can buy or adopt conventional methods extraction preparations such as steam distillation or dry distilling by market.The optium concentration of plant volatile oil is 1.5%-2.5%w/w, single using or mixing usefulness.
According to agents area, Borneolum Syntheticum or Mentholum are then used in choosing, and generally speaking, Mentholum is used for the heat-sensitive gel preparation for oral cavity and nasal cavity use; Borneolum Syntheticum then is used for the heat-sensitive gel preparation for rectum and vagina use.The optium concentration of Borneolum Syntheticum or Mentholum is 1.5%-2.5%w/w.
Ethanol is pharmaceutical ethanol, and specification is 95%, also can replace with medicinal dehydrated alcohol.Its preferred concentration is 10%w/w.
Poloxamer 407 solution refer to contain the phosphate buffered solution of 25%W/W poloxamer 407.Wherein solvent employing pH is the phosphate buffer of 5.0-7.0, the preparation of using for vagina wherein, preferably selecting pH is 5.0 phosphate buffer, and its compound method is: the pH value to 5.0 of regulating the sodium dihydrogen phosphate of 0.2mol/L with sodium hydroxide test solution (get the 4.3g sodium hydroxide and add 100ml water promptly).For the preparation that oral cavity or nasal cavity are used, preferably selecting pH is 7.0 phosphate buffer, and its compound method is: get potassium dihydrogen phosphate 0.68g, add 0.1mol/L sodium hydroxide solution 29.1ml, be diluted with water to 100ml promptly.The content of poloxamer 407 should be controlled at 25%w/w in poloxamer 407 solution, the too high or too low heat-sensitive gel character that all can influence preparation of the present invention, if use the content of poloxamer 407 to reach 30% poloxamer 407 solution, the preparation of the present invention that finally is mixed with at room temperature is can not mobile thick mastic; If use the content of poloxamer 407 to reach 20% poloxamer 407 solution, the preparation of the present invention that finally is mixed with still can flow under 37 ℃ of bath temperatures, and viscosity significantly reduces.
Antiseptic is an optional ingredient, and the use that can determine antiseptic according to the volatilization oil properties whether.The plant volatile oil that itself has antibacterial activity for Oleum Ocimi Gratissimi, patchouli oil, perilla oil, Oleum Anisi Stellati, Oleum Cinnamomi, fruit of cubeb litsea tree oil, Myrrha, Rhizoma Chuanxiong oil, Radix Angelicae Dahuricae oil, Oleum Folium Artemisiae Argyi, Herba Schizonepetae oil, Fructus Forsythiae oil, Oleum Citri Reticulatae, Herba Rosmarini Officinalis volatile oil etc. can not use antiseptic.Then can adopt antiseptic for Oleum Curcumae, Oleum Fructus Bruceae, Oleum menthae, Radix Angelicae Sinensis oil, Semen Juglandis distilling oil etc.Antiseptic can adopt methyl parahydroxybenzoate, ethyl ester, propyl ester, sorbic acid, potassium sorbate or chlorobutanol etc., wherein preferred propyl p-hydroxybenzoate.Optium concentration is 0.05%.
The characteristics of the preparation method of heat-sensitive gel preparation of the present invention are at first Borneolum Syntheticum or Mentholum to be dissolved in ethanol, then behind the alcoholic solution and the abundant mixing of plant volatile oil with Borneolum Syntheticum or Mentholum, add poloxamer 407 solution at last and prepare, specifically comprise the steps:
1. in phosphate buffer, add poloxamer 407, be mixed with the solution of 25w/w, standby.
2. take by weighing each component according to formula proportion, with Borneolum Syntheticum or Mentholum, antiseptic with dissolve with ethanol, add the abundant mixing of plant volatile oil again after, add the prepared poloxamer of step 1 407 solution again, evenly mixed, obtain free flowable translucent solution, i.e. the temperature-sensitive gel.
The packing of above thermal sensitive gel is selected: for the heat-sensitive gel preparation that vagina and rectum are used, select to adopt the disposable aluminum pipe of single dose, plastic tube, plastic bottle and vagina injector, pack.Use more convenient health.The thermal sensitive gel of using for oral cavity and nasal cavity, select the spray bottle packing of pressing or extruding, more can give play to the advantage of the thermal sensitive gel of the present invention's announcement: be liquid under the room temperature, can atomize that droplet becomes viscid semi-solid gel rapidly under the mucosa temperature influence.
It is freezing that heat-sensitive gel preparation of the present invention should be avoided in the preservation process.
Beneficial effect
1, mixes with poloxamer 407 solution again after the alcoholic solution combination of the present invention with the plant volatile oil of specific concentrations and Borneolum Syntheticum or Mentholum, improved the temperature-sensitive character of poloxamer 407 solution, resulting heat-sensitive gel preparation has the reversible mutual commentaries on classics characteristic of liquid/gel takes place under suitable temperature conditions responsive to temperature.Heat-sensitive gel preparation of the present invention liquid in a flowable at normal temperatures, and the reversibility phase transformation takes place near 28～33 ℃ of body temperature the time, form gel, can be applied to human body or animal cavity mucous membranes such as oral cavity, nasal cavity, rectum and vagina easily and effectively.
2, the present invention uses dissolve with ethanol earlier with Borneolum Syntheticum or Mentholum, becomes solution with the volatile oil mix homogeneously again, just can be dispersed in poloxamer 407 solution, and resulting heat-sensitive gel preparation has good stable, and storing 2 years can layering.
3, the volatile oil heat-sensitive gel of the present invention's preparation is easy to clean, and does not have greasy feeling.
The specific embodiment
Poloxamer 407 is available from Nanjing WeiEr chemical engineering Co., Ltd among the following embodiment.
Embodiment 1 each component is to the influence of phase transition temperature
Phase transition temperature assay method: with sample 3g, put in the 10ml test tube, put in the water-bath of controllable temperature, the built-in thermometer of test tube, the working sample temperature is from 25 ℃, 1 ℃ of every rising kept 3 minutes, and whether observation sample change into from flowable liquid can not mobile gel immediately.After undergoing phase transition, take out and put under the room temperature to observe whether revert to liquid, judge whether phase transformation is reversible.
Following sample is observed.
Experimental technique: get poloxamer 407 usefulness pH5.0 phosphate buffers and be mixed with 25% solution.With this solution is solvent, prepares following 5 samples respectively for test.
1. get the 0.75g Borneolum Syntheticum with the 4.0g dissolve with ethanol, add the above-mentioned pool of 34.4g and fall and stir evenly in the husky nurse solution.
2. get the 0.75g Borneolum Syntheticum with the 0.02g propyl p-hydroxybenzoate with the 4.0g dissolve with ethanol, add the above-mentioned pool of 34.4g and fall and stir evenly in the husky nurse solution.
3. getting the 0.82g Oleum Curcumae adds the above-mentioned pool of 34.4g and falls and stir evenly in the husky nurse solution.
4. get the 0.75g Borneolum Syntheticum with the 4.0g dissolve with ethanol, add the 0.82g Oleum Curcumae and stir evenly, add the above-mentioned pool of 34.4g and fall and stir evenly in the husky nurse solution.
5. get 0.75g Borneolum Syntheticum and 0.02g propyl p-hydroxybenzoate,, add the 0.82g Oleum Curcumae and stir evenly, add the above-mentioned pool of 34.4g and fall and stir evenly in the husky nurse solution with the 4.0g dissolve with ethanol.
Test result is as shown in the table
| Sample number into spectrum | Phase transition temperature | Whether reversible |
| 1 | Be heated to 37 ℃ and do not see that also phase transformation takes place | -- |
| 2 | Be heated to 37 ℃ and do not see that also phase transformation takes place | -- |
| 3 | Be heated to 37 ℃ and do not see that also phase transformation takes place | -- |
| 4 | 31℃ | Reversible |
| 5 | 29℃ | Reversible |
Test result shows: for the phosphate-buffered liquor of poloxamer 407, when alcoholic solution that adds Borneolum Syntheticum and Oleum Curcumae, can change its temperature-sensitive character, have suitable phase transition temperature; Simultaneously as can be seen, add the phase transition temperature that propyl p-hydroxybenzoate can change gel in the prescription, produce certain adverse effect.
Embodiment 2
Prescription (10) (g)
Fruit of cubeb litsea tree oil 0.84
Borneolum Syntheticum 0.75
Ethanol 4.0
Poloxamer 407 8.6
PH5.0 phosphate buffer 25.81
According to prescription, take by weighing each component, in the pH5.0 phosphate buffer, add poloxamer 407, stirring and dissolving.With the Borneolum Syntheticum dissolve with ethanol, gained solution and fruit of cubeb litsea tree oil mixing add resulting mixed liquor in poloxamer 407 solution, and constantly stir, and process for preparation can be finished under room temperature 15-25 ℃ condition.The gained mixed liquor is translucent flowable liquids.With each unit formulation 4g, be sub-packed in the disposable vaginal injector, add outer package.Inject in intravaginal during use.
Measure phase transition temperature according to embodiment 1 described method and be 29 ℃, reversible.
Embodiment 3
Prescription (10) (g)
Patchouli oil 0.84
Borneolum Syntheticum 0.75
Ethanol 4.0
Poloxamer 407 8.6
PH5.0 phosphate buffer 25.81
According to prescription, take by weighing each component, in the pH5.0 phosphate buffer, add poloxamer 407, stirring and dissolving.With the Borneolum Syntheticum dissolve with ethanol, gained solution and patchouli oil mixing add resulting mixed liquor in poloxamer 407 solution, and constantly stir, and process for preparation can be finished at ambient temperature.The gained mixed liquor is translucent flowable liquids.With each unit formulation 4g, be sub-packed in the disposable vaginal injector, add outer package.Inject in intravaginal during use.
Measure phase transition temperature according to embodiment 1 described method and be 29 ℃, reversible.
Embodiment 4
Prescription (10) (g)
Semen Juglandis distilling oil 0.82
Borneolum Syntheticum 0.75
Ethanol 2.0
Propylparaben 0.01
Poloxamer 407 4.1
PH5.0 phosphate buffer 1 2.3
According to prescription, take by weighing each component, in the pH5.0 phosphate buffer, add poloxamer 407, stirring and dissolving.Gained solution is transparent, even, flowable liquid under the room temperature.With Borneolum Syntheticum and propylparaben dissolve with ethanol, gained solution and Semen Juglandis distilling oil mixing add resulting mixed liquor in poloxamer 407 solution, and constantly stir, and process for preparation can be finished at ambient temperature.The gained mixed liquor is translucent flowable liquids.Press unit dose of 2g, be sub-packed in the disposable vaginal injector, packing.Inject in intravaginal during use.
Be 30 ℃ according to embodiment 1 described mensuration phase transition temperature, reversible.
Embodiment 5
Prescription (2) (g)
Oleum Ocimi Gratissimi 0.42
Mentholum 0.35
Ethanol 2.0
Poloxamer 407 4.1
PH7.0 phosphate buffer 1 2.3
According to prescription, take by weighing each component, in the pH7.0 phosphate buffer, add poloxamer 407, stirring and dissolving.Gained solution is transparent, even, flowable liquid under the room temperature.With the Mentholum dissolve with ethanol, gained solution and Oleum Ocimi Gratissimi mixing add resulting mixed liquor in poloxamer 407 solution, and constantly stir, and process for preparation can be finished at ambient temperature.The gained heat-sensitive gel is translucent flowable liquids.Press packing of 10g, be sub-packed in the high-density polyethylene plastics spray bottle.Spray a little during use in the oral ulcer wound.
Be 31 ℃ according to embodiment 1 described mensuration phase transition temperature, reversible.
Embodiment 6
Prescription (5) (g)
Fructus Cnidii oil 0.23
Radix Angelicae Sinensis oil 0.23
Borneolum Syntheticum 0.3
Ethanol 2.0
Propylparaben 0.01
Poloxamer 407 4.1
PH5.0 phosphate buffer 1 2.3
According to prescription, take by weighing each component, in the pH5.0 phosphate buffer, add poloxamer 407, stirring and dissolving.Gained solution is transparent, even, flowable liquid under the room temperature.With Borneolum Syntheticum and propylparaben dissolve with ethanol, gained solution and Fructus Cnidii oil, Radix Angelicae Sinensis oil mixing add resulting mixed liquor in poloxamer 407 solution, and constantly stir, and process for preparation can be finished at ambient temperature.The gained heat-sensitive gel is translucent flowable liquids.With each unit formulation 4g, be sub-packed in the disposable vaginal injector, add outer package.Inject in intravaginal during use.
Be 29 ℃ according to embodiment 1 described mensuration phase transition temperature, reversible.
Embodiment 7
Prescription (2) (g)
Oleum menthae 0.41
Mentholum 0.35
Ethanol 2.0
Potassium sorbate 0.01
Poloxamer 407 4.1
PH7.0 phosphate buffer 1 2.3
According to prescription, take by weighing each component, in the pH7.0 phosphate buffer, add poloxamer 407, stirring and dissolving.Gained solution is transparent, even, flowable liquid under the room temperature.With Mentholum and potassium sorbate dissolve with ethanol, gained solution and Oleum menthae mixing add resulting mixed liquor in poloxamer 407 solution, and constantly stir, and process for preparation can be finished at ambient temperature.The gained heat-sensitive gel is translucent flowable liquids.Press packing of 10g, be sub-packed in the high-density polyethylene plastics spray bottle.Spray a little during use in nasal cavity.
Be 30 ℃ according to embodiment 1 described mensuration phase transition temperature, reversible.
Embodiment 8
Prescription (10) (g)
Myrrha 0.51
Rhizoma Chuanxiong oil 0.51
Borneolum Syntheticum 0.55
Ethanol 4.0
Poloxamer 407 8.6
PH7.0 phosphate buffer 25.81
According to prescription, take by weighing each component, in the pH7.0 phosphate buffer, add poloxamer 407, stirring and dissolving.With the Borneolum Syntheticum dissolve with ethanol, gained solution and Myrrha, Rhizoma Chuanxiong oil mixing add resulting mixed liquor in poloxamer 407 solution, and constantly stir, and process for preparation can be finished at ambient temperature.The gained mixed liquor is translucent flowable liquids.With each unit formulation 4g, be sub-packed in the vasculiferous elastoplast bottle, add outer package.Clamp-on anal during use.
Measure phase transition temperature according to embodiment 1 described method and be 29 ℃, reversible.
Embodiment 9
Prescription (10) (g)
Herba Rosmarini Officinalis volatile oil 1.04
Borneolum Syntheticum 0.55
Ethanol 4.0
Poloxamer 407 8.6
PH7.0 phosphate buffer 25.81
According to prescription, take by weighing each component, in the pH7.0 phosphate buffer, add poloxamer 407, stirring and dissolving.With the Borneolum Syntheticum dissolve with ethanol, gained solution and Herba Rosmarini Officinalis volatile oil mixing add resulting mixed liquor in poloxamer 407 solution, and constantly stir, and process for preparation can be finished at ambient temperature.The gained mixed liquor is translucent flowable liquids.With each unit formulation 4g, be sub-packed in the vasculiferous elastoplast bottle, add outer package.Clamp-on anal during use.
Measure phase transition temperature according to embodiment 1 described method and be 29 ℃, reversible.
Claims (4)
1. heat-sensitive gel preparation, by weight, it consists of:
Plant volatile oil 1%～4%
Borneolum Syntheticum or Mentholum 1%～4%
Ethanol 8%～12%
Poloxamer 407 solution 81%～88%
Antiseptic 0%～0.07%
Wherein poloxamer 407 solution refer to contain the phosphate buffered solution of 25%w/w poloxamer 407.
2, heat-sensitive gel preparation according to claim 1, wherein plant volatile oil is Oleum Curcumae, Oleum Fructus Bruceae, Fructus Cnidii oil, Oleum Folium Artemisiae Argyi, Radix Angelicae Sinensis oil, Rhizoma Chuanxiong oil, Myrrha, Oleum Anisi Stellati, Oleum Ocimi Gratissimi, Oleum Cinnamomi, Oleum Camelliae, Oleum Eucalypti, Oleum menthae, patchouli oil, fruit of cubeb litsea tree oil, perilla oil, Semen Juglandis distilling oil, Herba Rosmarini Officinalis volatile oil, Radix Angelicae Dahuricae oil, Herba Schizonepetae oil, Fructus Forsythiae oil or Oleum Citri Reticulatae, single using or the mixing use.
3, heat-sensitive gel preparation according to claim 1, the pH that it is characterized in that phosphate buffered solution is 5.0～7.0.
4, the preparation method of the described heat-sensitive gel preparation of claim 1 may further comprise the steps:
(1) in phosphate buffer, add poloxamer 407, be mixed with the solution of 25%w/w, standby;
(2) take by weighing each component according to formula proportion, with Borneolum Syntheticum or Mentholum, antiseptic with dissolve with ethanol, add the abundant mixing of plant volatile oil again after, add prepared poloxamer 407 solution of step (1) again, evenly mixed, obtain free flowable translucent solution, i.e. the temperature-sensitive gel preparation.
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| CN109316550A (en) * | 2018-09-12 | 2019-02-12 | 广州有美生物技术有限公司 | A kind of cleaning is antibacterial to use care agent |
| CN109157566A (en) * | 2018-09-29 | 2019-01-08 | 南京依美生物科技有限公司 | A kind of gynecological gel preparation of anti-inflammation and sterilization and preparation method thereof |
| CN111297889A (en) * | 2020-02-28 | 2020-06-19 | 奥纳斯(北京)医药科技有限公司 | A composition for inhibiting gastrointestinal spasm and biliary system spasm, its aqueous solution and its preparation method |
| CN113209160A (en) * | 2021-05-14 | 2021-08-06 | 云南昭药健康产业有限公司 | Oral ulcer gel and preparation method thereof |
| CN113456581A (en) * | 2021-08-09 | 2021-10-01 | 信阳农林学院 | Rosemary essential oil nasal in-situ gel and preparation method and application thereof |
| CN113456581B (en) * | 2021-08-09 | 2024-02-02 | 信阳农林学院 | Rosemary essential oil nasal in-situ gel and preparation method and application thereof |
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