CN101933963A - Nasal in-situ gel for treating headache - Google Patents
Nasal in-situ gel for treating headache Download PDFInfo
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- CN101933963A CN101933963A CN 201010274137 CN201010274137A CN101933963A CN 101933963 A CN101933963 A CN 101933963A CN 201010274137 CN201010274137 CN 201010274137 CN 201010274137 A CN201010274137 A CN 201010274137A CN 101933963 A CN101933963 A CN 101933963A
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Abstract
The invention relates to a Chinese medicinal preparation prepared from the traditional Chinese medicines serving as raw materials, in particular to a nasal in-situ gel for treating headache. The in-situ gel comprises the following raw materials in percentage by weight: 5 to 15 percent of angelica dahurica extract, 1 to 5 percent of ligusticum chuanxiong hort oil, 1 to 5 percent of asarum oil, 0.05 to 0.15 percent of borneol, 10 to 20 percent of pH sensitive in-situ gel matrix, 3 to 10 percent of solubilizing agent, 0.5 to 1.5 percent of antioxidant, 1 to 5 percent of osmotic pressure regulator, 1 to 3 percent of mucosa absorption accelerator, 0.01 to 0.05 percent of metal complex and the balance of water. The in-situ gel can treat shaoyin headache, migraine caused by exopathic wind and air cooling headache with sharp pain and stringy and tight pulse.
Description
Technical field
The present invention relates to be shaped as with specific physical the pharmaceutical product of feature, being specifically related to Chinese medicine is the in-situ gel that raw material is made.
Background technology
With the increase of operating pressure, the sickness rate of headache has presented the situation of continuous rising with the quickening pace of modern life, has become puzzlement modern's commonly encountered diseases.According to incompletely statistics, the prevalence of China adult headache reaches 7.7%～18.7%, and wherein female patient is Duoed 3～4 times than the male patient, and majority is in adolescence.The outbreak of periodically having a headache can make the people dog-tired, and from economic angle, because several days cisco unity malfunctions, productivity ratio reduces, and has brought great burden for patient and society.The growth in anti-headache medicine market, the whole world is fast, and global anti-headache medicine sales volume was 300,000,000 dollars in 1991, and near 1,500,000,000 dollars, the average growth rate per annum in 1993～2000 years reached 40% by 1997.
China is world Chinese medicine big country, knows among the data base of office in state, relates to nearly 200 more than of the Chinese medicine preparation for the treatment of headache.Wherein, publication number is a kind of with the Borneolum Syntheticum monarch drug for the CN1546136A application for a patent for invention discloses, Rhizoma Acori Graminei, Rhizoma Chuanxiong and the Radix Angelicae Dahuricae are the oral formulations that ministerial drug causes, and this Chinese medicine preparation can be treated diseases such as migraine, tension headache, vascular headache and traumatic headache; Publication number a kind of for the CN1857425A application for a patent for invention discloses " medicine of treatment headache ", this medicine is made up of Herba Asari, the Radix Angelicae Dahuricae, Rhizoma Chuanxiong, Borneolum Syntheticum, Radix Polygalae and Radix Glycyrrhizae Six-element Chinese herb medicine, it is reasonable that all medicines share compatibility, cold expelling is arranged, dispel the wind, pain relieving, sensible effect can be treated the headache that multiple reason causes fast; Publication number is a kind of external herb mixture for the treatment of pain for the CN101229216A application for a patent for invention discloses, this mixture is an effective ingredient with Herba speranskiae tuberculatae, Radix Alangii, Herba Asari, the Radix Angelicae Dahuricae, Rhizoma Chuanxiong, Borneolum Syntheticum and peppermint essence, the medicine for external use that is caused has easy to use, rapid-action, the characteristics of determined curative effect, life-time service can reach the purpose of the pain pain that disappears.But,
CN1546136A application for a patent for invention scheme, the employing Borneolum Syntheticum is a monarch drug, the Radix Angelicae Dahuricae, Rhizoma Acori Graminei, Rhizoma Chuanxiong are that ministerial drug cures mainly migraine, tension headache, vascular headache and traumatic headache, and prescription drug is prepared into raw material medicated powder earlier, make granule, capsule, tablet and drop pill more respectively.Rhizoma Acori Graminei suffering, hardship in the prescription, temperature.GUIXIN, stomach warp.Effect removing dampness appetizing, the eliminating phlegm of having one's ideas straightened out, refreshment Fructus Alpiniae Oxyphyllae.It is not hungry to be used for the gastral cavity painful abdominal mass, mouthful dysentery of keeping silent, coma epilepsy, forgetful deafness.Being used for the treatment of the headache not as Herba Asari in clinical, use many.Said preparation adopts oral administration, and onset time postpones with respect to nasal-cavity administration, and bioavailability reduces.
Publication number is a CN1857425A application for a patent for invention scheme, and wherein Radix Polygalae is warm in nature, bitter in the mouth, suffering, have the Fructus Alpiniae Oxyphyllae of calming the nerves, eliminate the phlegm, the repercussive function, be used for insomnia and dreamful sleep, forgetful palpitation with fear that disarmony between the heart and kidney causes, staring spells more, expectoration is not well, sore swollen toxin, breast swell and pain.The Radix Glycyrrhizae invigorating the spleen and replenishing QI, heat-clearing and toxic substances removing, expelling phlegm for arresting cough, relieving spasm to stop pain, coordinating the actions of various ingredients in a prescription.Be used for weakness of the spleen and stomach, fatigue and weakness, shortness of breath and palpitation, cough with copious phlegm, gastral cavity abdomen, the anxious pain of extremity contraction, carbuncle sore tumefacting virus, cushion toxicity, strong.The record that is used to have a headache is few.And preparation is used as medicine for beating powder, can not get rid of the zest of medicated powder to nasal mucosa fully.
Publication number is that CN101229216A application for a patent for invention scheme is a kind of external preparation, and still, wherein used peppermint essence is aromatic drug, remedium corrigens and carminative.Can be used for skin or mucosa produces refrigerant sense and is not suitable for to alleviate.Herba speranskiae tuberculatae cures cold, traumatic injury, and skin infection, eczema, scabies are controlled in external.This medicine suffering, temperature, poisonous.But expelling wind and removing dampness, eliminating stasis to stop pain.Radix Alangii cures mainly the rheumatism bones and muscles pain, traumatic injury, and the two is little with headache relation, and preparation is percutaneous dosing, can not show a candle to nasal-cavity administration for the onset time and the bioavailability of treatment headache preparation.
Summary of the invention
In view of there is above-mentioned deficiency in prior art, technical problem to be solved by this invention provides a kind of Chinese medicine preparation of improved treatment headache.
The technical scheme that the present invention addresses the above problem is as described below:
A kind of nasal in-situ gel for the treatment of headache, contain following raw materials by weight percent in this in-situ gel: Radix Angelicae Dahuricae extract 5～15%, Rhizoma Chuanxiong oil 1～5%, Oleum Asari 1～5%, Borneolum Syntheticum 0.05～0.15%, pH responsive type situ-gel substrate 10～20%, solubilizing agent 3～10%, antioxidant 0.5～1.5%, osmotic pressure regulator 1～5%, mucosa absorption enhancer 1～3%, metal chelating agent 0.01～0.05%, all the other are water; Wherein
Described Radix Angelicae Dahuricae extract is prepared by following method: get the Radix Angelicae Dahuricae, add ultrasonic 15～30 minutes of 6～10 times of 70%～90% ethanol, decompression recycling ethanol, be concentrated into be equivalent to contain in every milliliter of medicinal liquid 2 the gram crude drug;
PH responsive type situ-gel substrate is carbomer;
Described solubilizing agent is a propylene glycol;
Described antioxidant is a sodium sulfite;
Described osmotic pressure regulator is a sodium chloride;
Described mucosa absorption enhancer is a sodium laurylsulfate;
Described metal chelating agent is EDTA-2Na.
In the such scheme of the present invention, described carbomer is carbomer 980 or carbomer 981.
In the such scheme of the present invention, the preferred for preparation method of described Radix Angelicae Dahuricae extract is: get the Radix Angelicae Dahuricae, add ultrasonic 20 minutes of 8 times of 75% ethanol, decompression recycling ethanol, be concentrated into be equivalent to contain in every milliliter of medicinal liquid 2 the gram crude drug.
Also containing percentage by weight in the in-situ gel of the present invention is 0.3～0.5% antiseptic, and described antiseptic is a chlorobutanol, and it has do not produce or only produce less nasal mucosa zest and the toxic advantage of cilium in the Mlc scope.
The preparation method of described in-situ gel of the present invention is made up of following steps:
In pH responsive type situ-gel substrate, add distilled water earlier and be stirred to abundant swelling, extract in the medicinal liquid to the Radix Angelicae Dahuricae in addition and add Oleum Asari, Rhizoma Chuanxiong oil, Borneolum Syntheticum, solubilizing agent, antioxidant, osmotic pressure regulator, mucosa absorption enhancer and metal chelating agent, be stirred to whole dissolvings, again institute's medicinal liquid is slowly joined in the abundant swollen situ-gel substrate and stir and afterwards add distilled water to 100%, add the pH regulator agent at last, pH value is transferred to 4.5, through 0.22 μ m filtering with microporous membrane degerming, in the nasal spray device of packing into promptly; Wherein, described pH regulator agent is a triethanolamine.
When containing antiseptic in the in-situ gel of the present invention, above-mentioned preparation method also has additional the step of dissolving antiseptic, this step specifically is before the adding distilled water is stirred to abundant swelling in pH responsive type situ-gel substrate, earlier antiseptic is dissolved in the used distilled water.
In the in-situ gel of the present invention, described Rhizoma Chuanxiong oil and Oleum Asari are commercially available vegetable oil, and wherein, described Rhizoma Chuanxiong oil is the vegetable oil that extracts in the Chinese crude drug Rhizoma Chuanxiong, and described Oleum Asari is the vegetable oil that extracts in the Chinese crude drug Herba Asari.Above-mentioned Rhizoma Chuanxiong oil and Oleum Asari also can method routinely be made by oneself, obtain as adopting steam distillation or supercritical carbon dioxide extraction method to extract volatile oil.
Effective ingredient in the in-situ gel of the present invention is Radix Angelicae Dahuricae extract, Rhizoma Chuanxiong oil, Oleum Asari and Borneolum Syntheticum, wherein, described Radix Angelicae Dahuricae extract is the ethanol extract of the Radix Angelicae Dahuricae, wherein contain coumarin kind compounds such as imperatorin and isoimperatorin, modern medicine study shows, the determined curative effect of coumarin compounds in treating headache; Described Rhizoma Chuanxiong oil is a Rhizoma Chuanxiong volatile oil, wherein contains ligustrazine, butylphthalide and 3-butyl-4,5-dihydro Phthalide etc., and described ligustrazine has the auxiliary treatment effect for headache; Described Oleum Asari is a Herba Asari volatile oil, wherein contain methyleugenol, asaricin, elemicin, safrole etc., described methyleugenol can improve brain microcirculation, make brain cell obtain competent oxygen and nutrient substance, and in time discharge its metabolite, stasis abreacting is with the double cerebral microcirculation disturbance of controlling; The crystallization that Borneolum Syntheticum is made by the distillation of the distillation extraction thing of canella, wherein the content of dextro Borneolum Syntheticum is up to 97.0%, have into the heart, lung meridian, the refreshment of having one's ideas straightened out, loose stagnated fire and reducing swelling and alleviating pain effect, pass the through brain of blood brain barrier to promote above-mentioned all medicines to see through bronchia mucosal, treatment SHAO YIN headache, diseases caused by exogenous pathogenic factor ailment said due to cold or exposure deflection aching all over the head, pain then as broken, faint and stringy pulse and tight air-cooled headache.
The specific embodiment
The equal weight percentage ratio of percentage ratio in the described prescription of following embodiment.
Example 1
Prescription:
Radix Angelicae Dahuricae extract 5%
Rhizoma Chuanxiong oil 2%
Oleum Asari 1%
Borneolum Syntheticum 0.05%
Carbomer 980 10%
Propylene glycol 1%
Sodium sulfite 0.5%
Sodium chloride 5%
Sodium laurylsulfate 1%
Antiseptic chlorobutanol 0.5%
Distilled water adds water to 100%
Method for making:
1) extraction of the Radix Angelicae Dahuricae: get the Radix Angelicae Dahuricae, add ultrasonic 25 minutes of 10 times of 80% ethanol, decompression recycling ethanol is concentrated into and is equivalent to contain in every milliliter of medicinal liquid 2 gram Radix Angelicae Dahuricae crude drug.
2) Rhizoma Chuanxiong oil is that the Chinese medicine Rhizoma Chuanxiong extracts the volatile oil that obtains with steam distillation, and Oleum Asari is that the Chinese medicine Herba Asari extracts the volatile oil that obtains with steam distillation.
3) preparation of situ-gel: carbomer 980 is added in the distilled water that is dissolved with the antiseptic chlorobutanol stir certain hour earlier, make it abundant swelling.Extract in addition and add Oleum Asari, Rhizoma Chuanxiong oil, Borneolum Syntheticum, solubilizing agent propylene glycol, mucosa absorption enhancer sodium laurylsulfate, antioxidant sodium sulfite, osmotic pressure regulator sodium chloride, metal chelating agent EDTA-2Na in the medicinal liquid and be stirred to whole dissolvings to the Radix Angelicae Dahuricae, at last medicinal liquid is slowly added in the carbomer gel and stir, regulate pH value to 4.5,0.22 μ m filtering with microporous membrane degerming with pH regulator agent sodium hydroxide.With filtered solution pack into in the nasal spray device of quantitative nozzle promptly.
Example 2
Prescription:
Radix Angelicae Dahuricae extract 10%
Rhizoma Chuanxiong oil 4%
Oleum Asari 2%
Borneolum Syntheticum 0.1%
Carbomer 980 15%
Propylene glycol 3%
Sodium sulfite 1%
Sodium chloride 2%
Sodium laurylsulfate 2%
Distilled water adds water to 100%
Method for making:
1) extraction of the Radix Angelicae Dahuricae: get the Radix Angelicae Dahuricae, add ultrasonic 25 minutes of 10 times of 80% ethanol, decompression recycling ethanol is concentrated into and is equivalent to contain in every milliliter of medicinal liquid 2 gram Radix Angelicae Dahuricae crude drug.
2) Rhizoma Chuanxiong oil is the volatile oil that the Chinese medicine Rhizoma Chuanxiong obtains with supercritical carbon dioxide extraction, and Oleum Asari is the volatile oil that the Chinese medicine Herba Asari obtains with supercritical carbon dioxide extraction.
3) preparation of situ-gel: carbomer 980 is added in the distilled water that is dissolved with the antiseptic chlorobutanol stir certain hour earlier, make it abundant swelling.Extract in addition and add Oleum Asari, Rhizoma Chuanxiong oil, Borneolum Syntheticum, solubilizing agent propylene glycol, mucosa absorption enhancer sodium laurylsulfate, antioxidant sodium sulfite, osmotic pressure regulator sodium chloride, metal chelating agent EDTA-2Na in the medicinal liquid and be stirred to whole dissolvings to the Radix Angelicae Dahuricae, at last medicinal liquid is slowly added in the carbomer gel and stir, regulate pH value to 4.0,0.22 μ m filtering with microporous membrane degerming with pH regulator agent sodium hydroxide.With filtered solution pack into in the nasal spray device of quantitative nozzle promptly.
Example 3
Prescription:
Radix Angelicae Dahuricae extract 15%
Rhizoma Chuanxiong oil 6%
Oleum Asari 3%
Borneolum Syntheticum 0.15%
Carbomer 980 20%
Propylene glycol 5%
Sodium sulfite 1.5%
Sodium chloride 3%
Sodium laurylsulfate 3%
Antiseptic chlorobutanol 0.5%
Distilled water adds water to 100%
Method for making:
1) extraction of the Radix Angelicae Dahuricae: get the Radix Angelicae Dahuricae, add ultrasonic 25 minutes of 10 times of 80% ethanol, decompression recycling ethanol is concentrated into and is equivalent to contain in every milliliter of medicinal liquid 2 gram Radix Angelicae Dahuricae crude drug.
2) Rhizoma Chuanxiong oil is that the Chinese medicine Rhizoma Chuanxiong extracts the volatile oil that obtains with steam distillation, and Oleum Asari is the volatile oil that the Chinese medicine Herba Asari obtains with supercritical carbon dioxide extraction.
3) preparation of situ-gel: carbomer 980 is added in the distilled water that is dissolved with the antiseptic chlorobutanol stir certain hour earlier, make it abundant swelling.Extract in addition and add Oleum Asari, Rhizoma Chuanxiong oil, Borneolum Syntheticum, solubilizing agent propylene glycol, mucosa absorption enhancer sodium laurylsulfate, antioxidant sodium sulfite, osmotic pressure regulator sodium chloride, metal chelating agent EDTA-2Na in the medicinal liquid and be stirred to whole dissolvings to the Radix Angelicae Dahuricae, at last medicinal liquid is slowly added in the carbomer gel and stir, regulate pH value to 4.5,0.22 μ m filtering with microporous membrane degerming with pH regulator agent sodium hydroxide.With filtered solution pack into in the nasal spray device of quantitative nozzle promptly.
Example 4
Prescription:
Radix Angelicae Dahuricae extract 5%
Rhizoma Chuanxiong oil 2%
Oleum Asari 1%
Borneolum Syntheticum 0.05%
Carbomer 980 20%
Propylene glycol 5%
Sodium sulfite 1.5%
Sodium chloride 3%
Sodium laurylsulfate 3%
Antiseptic chlorobutanol 0.5%
Distilled water adds water to 100%
Method for making:
1) extraction of the Radix Angelicae Dahuricae: get the Radix Angelicae Dahuricae, add ultrasonic 25 minutes of 10 times of 80% ethanol, decompression recycling ethanol is concentrated into and is equivalent to contain in every milliliter of medicinal liquid 2 gram Radix Angelicae Dahuricae crude drug.
2) Rhizoma Chuanxiong oil is the volatile oil that the Chinese medicine Rhizoma Chuanxiong is obtained with supercritical carbon dioxide extraction, and Oleum Asari is that Chinese medicine Herba Asari steam distillation extracts the volatile oil that obtains.
3) preparation of situ-gel: carbomer 980 is added in the distilled water that is dissolved with the antiseptic chlorobutanol stir certain hour earlier, make it abundant swelling.Extract in addition and add Oleum Asari, Rhizoma Chuanxiong oil, Borneolum Syntheticum, solubilizing agent propylene glycol, mucosa absorption enhancer sodium laurylsulfate, antioxidant sodium sulfite, osmotic pressure regulator sodium chloride, metal chelating agent EDTA-2Na in the medicinal liquid and be stirred to whole dissolvings to the Radix Angelicae Dahuricae, at last medicinal liquid is slowly added in the carbomer gel and stir, regulate pH value to 4.0,0.22 μ m filtering with microporous membrane degerming with pH regulator agent sodium hydroxide.With filtered solution pack into in the nasal spray device of quantitative nozzle promptly.
Example 5
Prescription:
Radix Angelicae Dahuricae extract 10%
Rhizoma Chuanxiong oil 4%
Oleum Asari 2%
Borneolum Syntheticum 0.1%
Carbomer 980 15%
Propylene glycol 2%
Sodium sulfite 0.75%
Sodium chloride 3%
Sodium laurylsulfate 2%
Antiseptic chlorobutanol 0.5%
Distilled water adds water to 100%
Method for making:
1) extraction of the Radix Angelicae Dahuricae: get the Radix Angelicae Dahuricae, add ultrasonic 25 minutes of 10 times of 80% ethanol, decompression recycling ethanol is concentrated into and is equivalent to contain in every milliliter of medicinal liquid 2 gram Radix Angelicae Dahuricae crude drug.
2) Rhizoma Chuanxiong oil is the volatile oil that the Chinese medicine Rhizoma Chuanxiong is obtained with supercritical carbon dioxide extraction, and Oleum Asari is that Chinese medicine Herba Asari steam distillation extracts the volatile oil that obtains.
3) preparation of situ-gel: carbomer 980 is added in the distilled water that is dissolved with the antiseptic chlorobutanol stir certain hour earlier, make it abundant swelling.Extract in addition and add Oleum Asari, Rhizoma Chuanxiong oil, Borneolum Syntheticum, solubilizing agent propylene glycol, mucosa absorption enhancer sodium laurylsulfate, antioxidant sodium sulfite, osmotic pressure regulator sodium chloride, metal chelating agent EDTA-2Na in the medicinal liquid and be stirred to whole dissolvings to the Radix Angelicae Dahuricae, at last medicinal liquid is slowly added in the carbomer gel and stir, regulate pH value to 4.5,0.22 μ m filtering with microporous membrane degerming with pH regulator agent sodium hydroxide.With filtered solution pack into in the nasal spray device of quantitative nozzle promptly.
Example 6
Prescription:
Radix Angelicae Dahuricae extract 15%
Rhizoma Chuanxiong oil 6%
Oleum Asari 3%
Borneolum Syntheticum 0.15%
Carbomer 980 20%
Propylene glycol 1%
Sodium sulfite 0.5%
Sodium chloride 2%
Sodium laurylsulfate 1%
Antiseptic chlorobutanol 0.5%
Distilled water adds water to 100%
Method for making:
1) extraction of the Radix Angelicae Dahuricae: get the Radix Angelicae Dahuricae, add ultrasonic 25 minutes of 10 times of 80% ethanol, decompression recycling ethanol is concentrated into and is equivalent to contain in every milliliter of medicinal liquid 2 gram Radix Angelicae Dahuricae crude drug.
2) Rhizoma Chuanxiong oil is the volatile oil that the Chinese medicine Rhizoma Chuanxiong obtains with supercritical carbon dioxide extraction, and Oleum Asari is the volatile oil that the Chinese medicine Herba Asari obtains with supercritical carbon dioxide extraction.
3) preparation of situ-gel: carbomer 980 is added in the distilled water that is dissolved with the antiseptic chlorobutanol stir certain hour earlier, make it abundant swelling.Extract in addition and add Oleum Asari, Rhizoma Chuanxiong oil, Borneolum Syntheticum, solubilizing agent propylene glycol, mucosa absorption enhancer sodium laurylsulfate, antioxidant sodium sulfite, osmotic pressure regulator sodium chloride, metal chelating agent EDTA-2Na in the medicinal liquid and be stirred to whole dissolvings to the Radix Angelicae Dahuricae, at last medicinal liquid is slowly added in the carbomer gel and stir, regulate pH value to 4.0,0.22 μ m filtering with microporous membrane degerming with pH regulator agent sodium hydroxide.With filtered solution pack into in the nasal spray device of quantitative nozzle promptly.
Example 7
Prescription:
Radix Angelicae Dahuricae extract 5%
Rhizoma Chuanxiong oil 2%
Oleum Asari 1%
Borneolum Syntheticum 0.05%
Carbomer 981 10%
Propylene glycol 1%
Sodium sulfite 0.5%
Sodium chloride 2%
Sodium laurylsulfate 1%
Antiseptic chlorobutanol 0.5%
Distilled water adds water to 100%
Method for making:
1) extraction of the Radix Angelicae Dahuricae: get the Radix Angelicae Dahuricae, add ultrasonic 20 minutes of 7 times of 75% ethanol, decompression recycling ethanol is concentrated into and is equivalent to contain in every milliliter of medicinal liquid 2 gram Radix Angelicae Dahuricae crude drug.
2) Rhizoma Chuanxiong oil is that the Chinese medicine Rhizoma Chuanxiong extracts the volatile oil that obtains with steam distillation, and Oleum Asari is that the Chinese medicine Herba Asari extracts the volatile oil that obtains with steam distillation.
3) preparation of situ-gel: carbomer 981 is added in the distilled water that is dissolved with the antiseptic chlorobutanol stir certain hour earlier, make it abundant swelling.Extract in addition and add Oleum Asari, Rhizoma Chuanxiong oil, Borneolum Syntheticum, solubilizing agent propylene glycol, mucosa absorption enhancer sodium laurylsulfate, antioxidant sodium sulfite, osmotic pressure regulator sodium chloride, metal chelating agent EDTA-2Na in the medicinal liquid and be stirred to whole dissolvings to the Radix Angelicae Dahuricae, at last medicinal liquid is slowly added in the carbomer gel and stir, regulate pH value to 4.5,0.22 μ m filtering with microporous membrane degerming with pH regulator agent sodium hydroxide.With filtered solution pack into in the nasal spray device of quantitative nozzle promptly.
Example 8
Prescription:
Radix Angelicae Dahuricae extract 10%
Rhizoma Chuanxiong oil 4%
Oleum Asari 2%
Borneolum Syntheticum 0.1%
Carbomer 981 15%
Propylene glycol 3%
Sodium sulfite 1%
Sodium chloride 3%
Sodium laurylsulfate 2%
Antiseptic chlorobutanol 0.5%
Distilled water adds water to 100%
Method for making:
1) extraction of the Radix Angelicae Dahuricae: get the Radix Angelicae Dahuricae, add ultrasonic 20 minutes of 7 times of 75% ethanol, decompression recycling ethanol is concentrated into and is equivalent to contain in every milliliter of medicinal liquid 2 gram Radix Angelicae Dahuricae crude drug.
2) Rhizoma Chuanxiong oil is the volatile oil that the Chinese medicine Rhizoma Chuanxiong obtains with supercritical carbon dioxide extraction, and Oleum Asari is the volatile oil that the Chinese medicine Herba Asari obtains with supercritical carbon dioxide extraction.
3) preparation of situ-gel: carbomer 981 is added in the distilled water that is dissolved with the antiseptic chlorobutanol stir certain hour earlier, make it abundant swelling.Extract in addition and add Oleum Asari, Rhizoma Chuanxiong oil, Borneolum Syntheticum, solubilizing agent propylene glycol, mucosa absorption enhancer sodium laurylsulfate, antioxidant sodium sulfite, osmotic pressure regulator sodium chloride, metal chelating agent EDTA-2Na in the medicinal liquid and be stirred to whole dissolvings to the Radix Angelicae Dahuricae, at last medicinal liquid is slowly added in the carbomer gel and stir, regulate pH value to 4.0,0.22 μ m filtering with microporous membrane degerming with pH regulator agent sodium hydroxide.With filtered solution pack into in the nasal spray device of quantitative nozzle promptly.
Example 9
Prescription:
Radix Angelicae Dahuricae extract 15%
Rhizoma Chuanxiong oil 6%
Oleum Asari 3%
Borneolum Syntheticum 0.15%
Carbomer 981 20%
Propylene glycol 5%
Sodium sulfite 1.5%
Sodium chloride 3%
Sodium laurylsulfate 3%
Antiseptic chlorobutanol 0.5%
Distilled water adds water to 100%
Method for making:
1) extraction of the Radix Angelicae Dahuricae: get the Radix Angelicae Dahuricae, add ultrasonic 20 minutes of 7 times of 75% ethanol, decompression recycling ethanol is concentrated into and is equivalent to contain in every milliliter of medicinal liquid 2 gram Radix Angelicae Dahuricae crude drug.
2) Rhizoma Chuanxiong oil is the volatile oil that the Chinese medicine Rhizoma Chuanxiong obtains with supercritical carbon dioxide extraction, and Oleum Asari is the volatile oil that the Chinese medicine Herba Asari obtains with supercritical carbon dioxide extraction.
3) preparation of situ-gel: carbomer 981 is added in the distilled water that is dissolved with the antiseptic chlorobutanol stir certain hour earlier, make it abundant swelling.Extract in addition and add Oleum Asari, Rhizoma Chuanxiong oil, Borneolum Syntheticum, solubilizing agent propylene glycol, mucosa absorption enhancer sodium laurylsulfate, antioxidant sodium sulfite, osmotic pressure regulator sodium chloride, metal chelating agent EDTA-2Na in the medicinal liquid and be stirred to whole dissolvings to the Radix Angelicae Dahuricae, at last medicinal liquid is slowly added in the carbomer gel and stir, regulate pH value to 4.5,0.22 μ m filtering with microporous membrane degerming with pH regulator agent sodium hydroxide.With filtered solution pack into in the nasal spray device of quantitative nozzle promptly.
Example 10
Prescription:
Radix Angelicae Dahuricae extract 5%
Rhizoma Chuanxiong oil 2%
Oleum Asari 1%
Borneolum Syntheticum 0.05%
Carbomer 981 20%
Propylene glycol 5%
Sodium sulfite 1.5%
Sodium chloride 3%
Sodium laurylsulfate 3%
Antiseptic chlorobutanol 0.5%
Distilled water adds water to 100%
Method for making:
1) extraction of the Radix Angelicae Dahuricae: get the Radix Angelicae Dahuricae, add ultrasonic 20 minutes of 7 times of 75% ethanol, decompression recycling ethanol is concentrated into and is equivalent to contain in every milliliter of medicinal liquid 2 gram Radix Angelicae Dahuricae crude drug.
2) Rhizoma Chuanxiong oil is that the Chinese medicine Rhizoma Chuanxiong extracts the volatile oil that obtains with steam distillation, and Oleum Asari is the volatile oil that the Chinese medicine Herba Asari obtains with supercritical carbon dioxide extraction.
3) preparation of situ-gel: carbomer 981 is added in the distilled water that is dissolved with the antiseptic chlorobutanol stir certain hour earlier, make it abundant swelling.Extract in addition and add Oleum Asari, Rhizoma Chuanxiong oil, Borneolum Syntheticum, solubilizing agent propylene glycol, mucosa absorption enhancer sodium laurylsulfate, antioxidant sodium sulfite, osmotic pressure regulator sodium chloride, metal chelating agent EDTA-2Na in the medicinal liquid and be stirred to whole dissolvings to the Radix Angelicae Dahuricae, at last medicinal liquid is slowly added in the carbomer gel and stir, regulate pH value to 4.0,0.22 μ m filtering with microporous membrane degerming with pH regulator agent sodium hydroxide.With filtered solution pack into in the nasal spray device of quantitative nozzle promptly.
Example 11
Prescription:
Radix Angelicae Dahuricae extract 10%
Rhizoma Chuanxiong oil 4%
Oleum Asari 2%
Borneolum Syntheticum 0.1%
Carbomer 981 15%
Propylene glycol 2%
Sodium sulfite 0.75%
Sodium chloride 3%
Sodium laurylsulfate 2%
Distilled water adds water to 100%
Method for making:
1) extraction of the Radix Angelicae Dahuricae: get the Radix Angelicae Dahuricae, add ultrasonic 20 minutes of 7 times of 75% ethanol, decompression recycling ethanol is concentrated into and is equivalent to contain in every milliliter of medicinal liquid 2 gram Radix Angelicae Dahuricae crude drug.
2) Rhizoma Chuanxiong oil is the volatile oil that the Chinese medicine Rhizoma Chuanxiong obtains with supercritical carbon dioxide extraction, and Oleum Asari is the volatile oil that the Chinese medicine Herba Asari obtains with supercritical carbon dioxide extraction.
3) preparation of situ-gel: carbomer 981 is added in the distilled water that is dissolved with the antiseptic chlorobutanol stir certain hour earlier, make it abundant swelling.Extract in addition and add Oleum Asari, Rhizoma Chuanxiong oil, Borneolum Syntheticum, solubilizing agent propylene glycol, mucosa absorption enhancer sodium laurylsulfate, antioxidant sodium sulfite, osmotic pressure regulator sodium chloride, metal chelating agent EDTA-2Na in the medicinal liquid and be stirred to whole dissolvings to the Radix Angelicae Dahuricae, at last medicinal liquid is slowly added in the carbomer gel and stir, regulate pH value to 4.5,0.22 μ m filtering with microporous membrane degerming with pH regulator agent sodium hydroxide.With filtered solution pack into in the nasal spray device of quantitative nozzle promptly.
Example 12
Prescription:
Radix Angelicae Dahuricae extract 15%
Rhizoma Chuanxiong oil 6%
Oleum Asari 3%
Borneolum Syntheticum 0.15%
Carbomer 981 20%
Propylene glycol 1%
Sodium sulfite 0.5%
Sodium chloride 3%
Sodium laurylsulfate 1%
Distilled water adds water to 100%
Method for making:
1) extraction of the Radix Angelicae Dahuricae: get the Radix Angelicae Dahuricae, add ultrasonic 20 minutes of 7 times of 75% ethanol, decompression recycling ethanol is concentrated into and is equivalent to contain in every milliliter of medicinal liquid 2 gram Radix Angelicae Dahuricae crude drug.
2) Rhizoma Chuanxiong oil is the volatile oil that the Chinese medicine Rhizoma Chuanxiong obtains with supercritical carbon dioxide extraction, and Oleum Asari is that the Chinese medicine Herba Asari extracts the volatile oil that obtains with steam distillation.
3) preparation of situ-gel: carbomer 981 is joined stir certain hour in the distilled water earlier, make it abundant swelling.Extract in addition and add Oleum Asari, Rhizoma Chuanxiong oil, Borneolum Syntheticum, solubilizing agent propylene glycol, mucosa absorption enhancer sodium laurylsulfate, antioxidant sodium sulfite, osmotic pressure regulator sodium chloride, metal chelating agent EDTA-2Na in the medicinal liquid and be stirred to whole dissolvings to the Radix Angelicae Dahuricae, at last medicinal liquid is slowly added in the carbomer gel and stir, regulate pH value to 4.0,0.22 μ m filtering with microporous membrane degerming with pH regulator agent sodium hydroxide.With filtered solution pack into in the nasal spray device of quantitative nozzle promptly.
Example 51 effect researchs example
The inventor has carried out toxicity, pharmacodynamics test to institute's invention product.
One, nasal ciliary toxicity is investigated
It is fixing that Bufo siccus is lain on the back, the oral cavity is opened and fixing, drip prepared medicinal liquid 0.5ml in palate mucosa place and make complete submergence palate, contact after 30 or 60 minutes and clean medicine, separate the palate mucosa with normal saline, get about 3mm * 3mm size, clean clot and foreign material with normal saline immediately, mucosa towards on be tiled on the microscope slide, drip normal saline, covered is with 400 times of observation by light microscope ciliary movement situations.Subsequently microscope slide is held on and is added with in the water saturated chromatography cylinder of a small amount of distillation, airtight, place room temperature environment, after this take out specimen at regular intervals, put microscopically and observe, until the cilium stop motion, the time of record cilium persistent movement.Normal saline 0.5ml in contrast, other operational approach is the same.With cilium persistent movement time cilium persistent movement time of administration group, obtain the relative percentage of cilium persistent movement time divided by the normal saline matched group.Acetonideexample 1～12 prepared test agent that supplies is subjected to test solution all less to the toxicity of Bufo siccus maxillary mucosa cilium, and the relative percentage of cilium persistent movement time is 95.3 ± 2.40%, and the extent of damage is slightly had any different with the drug level difference.
Two, pharmacodynamics test
1 laboratory animal
Healthy kunming mice, male and female half and half, body weight 18-25g.
2 methods
2.1 experimental technique
2.1.2 acetic acid twisting method
With 60 mices, be divided into 6 groups at random, 10 every, weigh and number.The A group is physiology saline control group, and nasal cavity gives 0.8g/kg (body weight) normal saline, at administration 5min pneumoretroperitoneum injection acetum; The B group is oral matched group, irritates stomach and gives 1.2g/kg (body weight) root of Dahurian angelica ice medicinal liquid (embodiment 1), 30min lumbar injection acetum after the administration; C group, D group, E organize nasal-cavity administration, and used medicine is respectively the in-situ gel of embodiment 1,2,3, and dosage is 0.8g/kg, at administration 5min pneumoretroperitoneum injection acetum.It is 0.1ml that every mice is lumbar injection 0.6% acetum.F group is for being the prescription of CN 1284575C patent of invention with reference to publication number, the matched group that the preparation technology of patent situ-gel according to the present invention (embodiment 1) makes, and giving dosage is 0.8g/kg.
2.1.2 hot plate method
Selection is reflected at 5～30s person, 60 mices to 50 ℃ of hot plate pains sensation, is divided into 6 groups at random, 10 every group.The A group is physiology saline control group, and nasal cavity gives normal saline; The B group is oral matched group, irritates stomach and gives 1.2g/kg root of Dahurian angelica ice medicinal liquid; C group, D group, E organize nasal-cavity administration, and used medicine is respectively the in-situ gel of embodiment 1,2,3, and dosage is 0.8g/kg.F group is for being the prescription of CN 1284575C patent of invention with reference to publication number, the matched group that the preparation technology of patent situ-gel according to the present invention (embodiment 1) makes, and giving dosage is 0.8g/kg.
2.2 observation index and assay method
2.2.1 acetic acid twisting method
Observe and record injection acetum after the number of times that occurs writhing response in time of body and the 20min appears turning round, and calculate the analgesia rate according to following formula:
2.2.2 hot plate method
15min, 30min, 60min, 90min measure the pain response latency before every mice administration and after the administration, calculate threshold of pain raising rate according to following formula:
2.3 date processing
Relatively use the methods analyst of folk prescription to variance analysis (One-way ANOVA), data Spss13.0 software processes between each group between the observation index.
3 results
3.1 acetic acid twisting method
The time of body appears turning round in each treated animal, the inferior analgesia rate that reaches of body of turning round in the 20min sees Table 1.
The influence that table 1 root of Dahurian angelica ice field position gel reacts the mice acetic acid twisting (
N=10)
Annotate: compare with matched group,
*P＜0.05,
*P＜0.01; Compare with root of Dahurian angelica ice medicinal liquid group,
#P＜0.05,
##P＜0.01; Compare with high dose group,
△P＜0.05,
△ △P＜0.01.
By table 1 result, from mice turn round the body number of times, each administration group is compared with the blank group, and significant difference (P＜0.01) is all arranged, and illustrates that each treatment group has significantly reduced the pain reaction of mice; Compare with root of Dahurian angelica ice medicinal liquid group, C organizes there was no significant difference (P＞0.05), and D group and E group all have significant difference (P＜0.01), illustrate under the situation of Isodose, and the analgesic effect of icing the oral administration of medicinal liquid for the nasal-cavity administration of test agent than the root of Dahurian angelica strengthens; Compare with the E group, C group and D group all have significant difference (P＜0.01), and the increase along with dosage is described, for the analgesic effect enhancing of test agent.Time of body occurs turning round from mice, each administration group is compared with the blank group, and significant difference (P＜0.01) is all arranged, and illustrates that each treatment group has delayed the time that pain reaction appears in mice; Compare with root of Dahurian angelica ice medicinal liquid group, C organizes there was no significant difference (P＞0.05), and D group and E group all have significant difference (P＜0.01), illustrates under the situation of Isodose, and the oral administration mice that the nasal-cavity administration of confession test agent is iced medicinal liquid than the root of Dahurian angelica pain reaction time occurs and will prolong; Compare with the E group, C group and D group all have significant difference (P＜0.01), and the increase along with dosage is described, the effect enhancing of pain reaction occurs for the inhibition of test agent.The F group also can reduce the pain reaction of mice, but effect is worse than root of Dahurian angelica ice field position gel group.
The result of calculation of analgesia rate is compared with root of Dahurian angelica ice medicinal liquid group, and it is about 17% that the D group has improved, and the E group has improved about 24%.The F group also increases, but effect is worse than the experimental group that uses in-situ gel of the present invention.
3.2 hot plate method
Pain threshold, threshold of pain raising rate before and after each treated animal administration see Table 2.
Table 2 root of Dahurian angelica ice field position gel causes the influence (n=10) of pain reaction to the mice hot plate
Annotate: compare with matched group,
*P＜0.05,
*P＜0.01; Compare with root of Dahurian angelica ice medicinal liquid group,
#P＜0.05,
##P＜0.01; Compare with the E group,
△P＜0.05,
△ △P＜0.01.
As shown in Table 2, each administration group is compared with the blank group, and the threshold of pain raising rate of each time point all has significant difference (P＜0.01), illustrates that the pain of each administration group mice all is effectively suppressed; Treatment group for test agent is compared with the treatment group of root of Dahurian angelica ice medicinal liquid, and the threshold of pain raising rate of each time point all has significant difference (P＜0.01), illustrates to supply test agent that the analgesic activity of mice is higher than root of Dahurian angelica ice medicinal liquid; Compare with the E group with the D group for test agent C group, the threshold of pain raising rate of each time point all has significant difference (P＜0.01), illustrates that the curative effect that increases for test agent along with dosage strengthens.3 treatment groups for test agent increase and increase along with the time when pain threshold raising rate begins, and when having arrived 30min, prolong in time, and pain threshold maintains on the level substantially; The speed that root of Dahurian angelica ice administering medical liquids group pain threshold raising rate then raises in time is slow, this to a certain extent also prompting for the administration of test agent via intranasal application after effective ingredient to enter the speed that body circulation speed will more oral root of Dahurian angelica ice medicinal liquid fast.The F group also increases, but effect is worse than the experimental group that uses in-situ gel of the present invention.
Claims (5)
1. nasal in-situ gel for the treatment of headache, contain following raw materials by weight percent in this in-situ gel: Radix Angelicae Dahuricae extract 5～15%, Rhizoma Chuanxiong oil 1～5%, Oleum Asari 1～5%, Borneolum Syntheticum 0.05～0.15%, pH responsive type situ-gel substrate 10～20%, solubilizing agent 3～10%, antioxidant 0.5～1.5%, osmotic pressure regulator 1～5%, mucosa absorption enhancer 1～3%, metal chelating agent 0.01～0.05%, all the other are water.Wherein
Described Radix Angelicae Dahuricae extract is prepared by following method: get the Radix Angelicae Dahuricae, add ultrasonic 15～30 minutes of 6～10 times of 70%～90% ethanol, decompression recycling ethanol, be concentrated into be equivalent to contain in every milliliter of medicinal liquid 2 the gram crude drug;
PH responsive type situ-gel substrate is carbomer;
Described solubilizing agent is a propylene glycol;
Described antioxidant is a sodium sulfite;
Described osmotic pressure regulator is a sodium chloride;
Described mucosa absorption enhancer is a sodium laurylsulfate;
Described metal chelating agent is EDTA-2Na.
2. a kind of nasal in-situ gel for the treatment of headache according to claim 1 is characterized in that, also containing percentage by weight in the described in-situ gel is 0.3～0.5% antiseptic; Described antiseptic is a chlorobutanol.
3. a kind of nasal in-situ gel for the treatment of headache according to claim 1 and 2, it is characterized in that, described Radix Angelicae Dahuricae extract is prepared by following method: get the Radix Angelicae Dahuricae, add ultrasonic 20 minutes of 8 times of 75% ethanol, decompression recycling ethanol, be concentrated into be equivalent to contain in every milliliter of medicinal liquid 2 the gram crude drug.
4. method for preparing nasal in-situ gel as claimed in claim 1, this method is made up of following steps:
In pH responsive type situ-gel substrate, add distilled water earlier and be stirred to abundant swelling, extract in the medicinal liquid to the Radix Angelicae Dahuricae in addition and add Oleum Asari, Rhizoma Chuanxiong oil, Borneolum Syntheticum, solubilizing agent, antioxidant, osmotic pressure regulator, mucosa absorption enhancer and metal chelating agent, be stirred to whole dissolvings, again institute's medicinal liquid is slowly joined in the abundant swollen situ-gel substrate and stir and afterwards add distilled water to 100%, add the pH regulator agent at last, pH value is transferred to 4.5, through 0.22 μ m filtering with microporous membrane degerming, in the nasal spray device of packing into promptly; Wherein, described pH regulator agent is a triethanolamine.
5. method for preparing nasal in-situ gel as claimed in claim 2, this method comprises the described step of claim 4, it is characterized in that, the adding step that also comprises antiseptic, this step is before the adding distilled water is stirred to abundant swelling in pH responsive type situ-gel substrate, earlier antiseptic is dissolved in the used distilled water.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103239494A (en) * | 2013-05-30 | 2013-08-14 | 南京海思创新生物科技有限公司 | Nasal spray composition for treating migraine and preparation method thereof |
| CN106361699A (en) * | 2016-08-25 | 2017-02-01 | 江苏长泰药业有限公司 | Nasal spray product for treating or preventing cold and application thereof |
| CN108324688A (en) * | 2018-04-11 | 2018-07-27 | 苏州大学 | Lizakuputan benzoate situ-gel nasal spray |
| CN112316062A (en) * | 2020-11-17 | 2021-02-05 | 吉林大学中日联谊医院 | Traditional Chinese medicine composition for treating migraine, nasal gel, preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1116545A (en) * | 1995-04-07 | 1996-02-14 | 唐道臣 | Brain-refreshing analgesic powder medicine |
| CN1857425A (en) * | 2006-03-16 | 2006-11-08 | 张新生 | Headache treating medicine |
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2010
- 2010-09-03 CN CN2010102741378A patent/CN101933963B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1116545A (en) * | 1995-04-07 | 1996-02-14 | 唐道臣 | Brain-refreshing analgesic powder medicine |
| CN1857425A (en) * | 2006-03-16 | 2006-11-08 | 张新生 | Headache treating medicine |
Non-Patent Citations (1)
| Title |
|---|
| 《山东中医杂志》 20000731 陈庆生 镇痛散治疗偏头痛 第440页 权利要求1-5 第19卷, 第7期 2 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103239494A (en) * | 2013-05-30 | 2013-08-14 | 南京海思创新生物科技有限公司 | Nasal spray composition for treating migraine and preparation method thereof |
| CN103239494B (en) * | 2013-05-30 | 2014-09-10 | 南京海思创新生物科技有限公司 | Nasal spray composition for treating migraine and preparation method thereof |
| CN106361699A (en) * | 2016-08-25 | 2017-02-01 | 江苏长泰药业有限公司 | Nasal spray product for treating or preventing cold and application thereof |
| CN108324688A (en) * | 2018-04-11 | 2018-07-27 | 苏州大学 | Lizakuputan benzoate situ-gel nasal spray |
| CN112316062A (en) * | 2020-11-17 | 2021-02-05 | 吉林大学中日联谊医院 | Traditional Chinese medicine composition for treating migraine, nasal gel, preparation method and application |
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| CN101933963B (en) | 2011-09-14 |
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