CN112316062A - Traditional Chinese medicine composition for treating migraine, nasal gel, preparation method and application - Google Patents
Traditional Chinese medicine composition for treating migraine, nasal gel, preparation method and application Download PDFInfo
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- CN112316062A CN112316062A CN202011287170.4A CN202011287170A CN112316062A CN 112316062 A CN112316062 A CN 112316062A CN 202011287170 A CN202011287170 A CN 202011287170A CN 112316062 A CN112316062 A CN 112316062A
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- 239000005526 vasoconstrictor agent Substances 0.000 description 1
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- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/72—Rhamnaceae (Buckthorn family), e.g. buckthorn, chewstick or umbrella-tree
- A61K36/725—Ziziphus, e.g. jujube
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- A61K36/88—Liliopsida (monocotyledons)
- A61K36/898—Orchidaceae (Orchid family)
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Abstract
The invention is applicable to the technical field of medicines, and provides a traditional Chinese medicine composition for treating migraine, a nasal gel, a preparation method and an application thereof, wherein the traditional Chinese medicine composition comprises the following components in parts by weight: 10-18 parts of ligusticum wallichii extract, 0.5-2 parts of gastrodia elata extract, 1-5 parts of spina date seed extract and 1-3 parts of menthol. On the basis of a classical prescription 'Dachuanxiong rhizome prescription' for treating migraine, the wild jujube seeds are used for playing a synergistic and complementary role, and the mint is used for inducing resuscitation and promoting penetration, so that the traditional Chinese medicine composition accords with the relevant principle of traditional Chinese medicine compatibility; the nasal gel prepared from the traditional Chinese medicine composition has small side effect and high safety, is superior to the traditional prescription in the aspects of quickly relieving headache symptoms, relieving duration, stabilizing and reliability in curative effect and the like, can be used for medicine production practice, and is an ideal prescription hopefully replacing the traditional oral preparation.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a traditional Chinese medicine composition for treating migraine, a nasal gel, a preparation method and application thereof.
Background
Headache is a common clinical symptom, and is generally pain in the upper part of the skull (the upper part of the eyebrow arch, the upper part of the pinna, above the line connecting the prominences of the occipital surface). The migraine is a recurrent headache, which is mostly a side-pulsating headache, often accompanied by symptoms such as nausea and vomiting. According to statistics, the 1-year prevalence rate of migraine is about 9.3%, most women are common and can develop the disease at any age, and the prevalence rate is higher between 40 and 49 years old. The disability rate of the disease is high, the burden is heavy, and the life and the work of more than half of patients are seriously influenced.
The cause of migraine is not clear at present, and it is thought that migraine is caused by imbalance in excitation/inhibition balance of central nervous system due to complex interaction among multiple susceptible genes, susceptible genes and environmental factors, and trigeminal vascular pathways are repeatedly activated and abnormally sensitized, thereby causing headache attack and other accompanying symptoms. Modern medicine has two modes of drug treatment and non-drug treatment for treating migraine, and drug treatment is divided into emergency treatment and prevention treatment. The following three classes of drugs are mainly used for acute episodes: vasoconstrictors: ergotamine and dihydroergotamine are the current classical drugs for treating migraine; antipyretic analgesic drugs: mainly refers to non-steroidal anti-inflammatory drugs, aspirin, ibuprofen and p-hexanoamidophenol, and is a preferred analgesic for mild and moderate migraine attacks; selective 5-HT receptor agonists: like triptans, the side effect is small, and the medicine is an emerging specific medicine for treating migraine. Although a plurality of medicines are used for preventing and treating migraine, although the symptoms of migraine of a patient can be relieved to different degrees, the migraine cannot be cured radically, the medicines still need to be taken, and the side effects are not ignored.
The traditional Chinese medicine considers that the pathogenesis of the migraine lies in unsmooth qi movement and blood stasis and collateral obstruction caused by external infection or internal injury. The ' Dachuanxiong rhizome formula ' developed according to the Chinese medicine theory is a famous prescription for treating migraine, and is from the book II of the ' Yi Ming Lun Fang ' of the ' Jine Liu Jing essence, and consists of two medicines of chuanxiong rhizome and gastrodia elata. The gastrodia elata can stop wind and relieve pain, and the ligusticum wallichii can activate blood and promote qi, the combination of the gastrodia elata and the ligusticum wallichii has good treatment effect on treating headache symptoms caused by blood stasis blocking and wind-yang rising, the prescription is simple and accurate in treatment effect, and the addition and subtraction of the medicinal flavor can be carried out according to different symptoms of patients, the compatibility is reasonable, and the treatment is carried out according to the syndrome differentiation, so that the purposes of promoting qi and relieving pain are achieved. However, the traditional Chinese medicine formula has the problems of general curative effect, inconvenient use and the like.
In addition, most of the existing Chinese patent medicines for treating migraine are orally taken, and the nasal administration preparations are less. The nasal drug delivery system is a preparation which is used in the nasal cavity and absorbed through the nasal mucosa to exert a local or systemic therapeutic action. In recent years, with the application of new auxiliary materials and new treatment technologies, the nasal administration preparation is increasingly paid more attention by people and becomes one of the research hotspots in the field of current pharmaceutics.
The nasal gel is a gel-like nasal semisolid preparation prepared from the medicine and proper auxiliary materials. The nasal gel is administrated through the nasal cavity, the gel is directly used for the nasal cavity, and through the movement of small molecules, the effective component medicine enters the blood through the dense venous plexus of the nasal cavity and can bypass the blood brain barrier to directly deliver the medicine into the brain, so the nasal gel has the advantages of quick response, long action time, avoidance of liver first pass effect, high bioavailability and the like, is superior to the traditional prescription in the aspects of quick relief of headache symptoms, duration relief, stable and reliable curative effect and the like, and is an effective and feasible administration mode. The currently marketed hydroergotamine preparation has a nasal preparation, and has good curative effect and market reaction. The improved formula of the chuanxiong rhizome is prepared into a nasal administration preparation, and provides a new idea and way for treating migraine by using the traditional Chinese medicine.
In summary, the current treatment for migraine can be divided into acute-phase treatment and prevention treatment, and some acute-phase treatment drugs such as non-steroidal anti-inflammatory drugs can have adverse reactions to gastrointestinal tract, allergy, granulocytopenia and other side effects; contraindications of specific analgesic drugs are complex; improper course of administration can also lead to drug dependence or conversion to drug abuse headache and chronic migraine. In addition, currently, oral liquids, capsules and tablets prepared according to the formula of the large ligusticum wallichii on the market are various, and the preparations for oral administration cannot quickly relieve headache symptoms because of slow effect.
Disclosure of Invention
The embodiment of the invention aims to provide a traditional Chinese medicine composition for treating migraine, and aims to solve the problems in the background art.
The embodiment of the invention is realized in such a way that the traditional Chinese medicine composition for treating migraine comprises the following components in parts by weight: 10-18 parts of ligusticum wallichii extract, 0.5-2 parts of gastrodia elata extract, 1-5 parts of spina date seed extract and 1-3 parts of menthol.
As a preferred scheme of the embodiment of the invention, the traditional Chinese medicine composition comprises the following components in parts by weight: 13-15 parts of ligusticum wallichii extract, 1-1.5 parts of gastrodia elata extract, 2-3 parts of spina date seed extract and 1.5-2.5 parts of menthol.
As another preferable scheme of the embodiment of the present invention, the ligusticum wallichii extract, the gastrodia elata extract and the spina date seed extract are all ethanol extracts.
In the formula, the rhizoma Ligustici Chuanxiong is dried rhizome of Umbelliferae plant rhizoma Ligustici Chuanxiong, and has fragrant and thick smell, bitter and pungent taste, pungent and warm nature, belongs to liver, gallbladder and pericardium channels, and has effects of promoting blood circulation, activating qi-flowing, dispelling pathogenic wind and relieving pain. Based on the effective components and pharmacological action, the main effective component of the ligusticum wallichii is ferulic acid, and has various effects of removing oxygen free radicals, calcium antagonism, expanding blood vessels, resisting platelet aggregation and the like.
Rhizoma Gastrodiae is dry tuber of Gastrodia elata Blume of Orchidaceae, has effects of calming endogenous wind and relieving spasm, suppressing liver yang, dispelling pathogenic wind and dredging collaterals, and is suitable for headache, giddiness, limbs anesthesia, infantile convulsion, convulsive epilepsy, and tetany etc. Gastrodin is the main effective component of rhizoma gastrodiae, has various pharmacological actions such as pain easing, sedation and the like, so that the traditional large rhizoma ligustici wallichii prescription has obvious prevention and treatment effect on migraine by matching rhizoma ligustici wallichii and rhizoma gastrodiae.
The spina date seed is a dry and mature seed of a Rhamnaceae plant ziziphus jujube, has the effects of nourishing the heart and the liver, calming the heart and soothing the nerves, arresting sweating and promoting the production of body fluid and the like, is a key medicine for soothing the nerves in traditional Chinese medicine, and is mainly used for treating different insomnia, depression, neurasthenia, tension headache, dizziness and other symptoms in modern clinic. Based on the pharmacological action of spina date seeds, spina date seed saponin (spina date seed saponin A, B) which is a spina date seed extract is a main drug effect component with the tranquilizing and allaying excitement effect. Therefore, the spina date seed and the large ligusticum wallichii prescription are used for compatibility to play a role in nourishing blood and soothing nerves, and play a role in synergy and assistance in treating headache and accompanying symptoms.
The mint is cool in nature, warm and pungent in smell, non-toxic, belongs to a medicine for inducing resuscitation and promoting penetration, and can enter lung, liver and heart channels, has the effects of dispelling wind and heat, clearing head and eyes, detoxifying and the like, and can promote the medicines to pass through a blood brain barrier through nasal mucosa and directly reach the brain, so that the curative effect of targeted treatment of the brain is achieved. The formula directly adopts mint extracts: menthol. Menthol is a pure traditional Chinese medicine extract, is safe and nontoxic, has better permeation promoting effect on skin and mucosa, can especially shorten the action time of the medicine, and can improve the smell of the preparation due to the fragrance of the menthol.
In addition, gastrodin is an effective component required by the gastrodia elata, belongs to a phenolic glycoside, has small molecular weight and high polarity, and can be extracted by water and alcohol. However, the gastrodia elata contains more starch, and the water decoction is sticky and not beneficial to the diffusion and dissolution of effective components; in the concentration process, the liquid medicine becomes more viscous along with the concentration, is easy to adhere to the wall of the container, and is difficult to operate; also brings great difficulty to purification and refining. Therefore, the gastrodia elata can be extracted by ethanol reflux.
Ferulic acid is an effective component of ligusticum wallichii in the formula, ferulic acid has a chemical name of 3-methoxy-4-hydroxycinnamic acid, has cis form and trans form, wherein the cis form is yellow oily matter, the trans form is square crystal or fiber crystal, the melting point is 174 ℃, and the ferulic acid is dissolved in hot water, ethanol and ethyl acetate, is slightly dissolved in ether and is difficultly dissolved in benzene and petroleum ether; therefore, the organic solvent ethanol is often selected for extraction.
The spina date seed extract spina date seed saponin is a main drug effect component with the tranquilizing and allaying excitement effect, the saponin compound has higher solubility in an ethanol water solution, the extraction rate of active substances with small polarity is higher than that of water, and the ethanol has the advantages of safety, no toxicity, low price and the like and is a common solvent for extracting the saponin compound. Therefore, according to the physicochemical properties of the medicinal materials in the formula and the requirements of clinical medication, the effective components of the medicinal components in the formula can be extracted according to an alcohol extraction method. Through a large amount of literature search and experimental research, on the basis of a single-factor test, the volume fraction of ethanol, the amount of ethanol, the extraction times and the extraction time are generally used as investigation conditions, so that the investigation factors of the experiment are determined, orthogonal experiment design is carried out, and the process conditions with high extraction rate are screened out. Because the molecular structure and the physicochemical property of each medicinal component are different, the medicinal components are respectively extracted by orthogonal experimental screening and extraction methods, so that the ligusticum wallichii, the gastrodia elata and the spina date seed of the formula are respectively extracted to obtain respective effect components.
The nasal cavity administration preparation has small drug-loading rate, and further purification of ethanol extract is required. The macroporous resin is widely applied in the separation and purification process of the effective components of the traditional Chinese medicine, has the advantages of good purification effect, simple and convenient regeneration and the like, and thus the extract is purified by utilizing the macroporous resin. In addition, an orthogonal design method can be adopted, the content of each drug extract is used as an evaluation index, and the volume fraction of ethanol, the ethanol dosage, the extraction times and the extraction time are used as investigation factors to screen out the optimal process.
Specifically, gastrodin extraction: accurately weighing a certain amount of rhizoma Gastrodiae, placing in a round bottom flask, adding ethanol solution with a certain volume fraction according to the conditions of an orthogonal test table, reflux-extracting, filtering while hot, mixing filtrates, cooling the solution, adding corresponding solvent to a constant volume, and shaking. And (3) designing according to an orthogonal test method, analyzing the orthogonal test result by adopting a direct analysis method, taking the gastrodin content as an index, obtaining the influence of each factor of the volume fraction of ethanol, the ethanol dosage, the extraction times and the extraction time through variance analysis, and screening the gastrodin extraction process on the basis.
Similarly, the content of ferulic acid of the ligusticum wallichii extract and the content of spina date seed saponin of the spina date seed extract are respectively used as evaluation indexes, and the influence of the volume fraction of ethanol, the amount of ethanol, the extraction time and the extraction frequency on the extraction process is examined through an orthogonal test, so that the extraction processes of the ferulic acid and the spina date seed saponin are preferably selected.
Another object of the present invention is to provide a nasal gel containing the above-mentioned Chinese medicinal composition.
The gel matrix generally comprises water, glycerol or propylene glycol, cellulose derivatives or carbomer and the like, and in consideration of the properties of the medicine and the stability of the preparation, auxiliary materials such as a humectant, a solubilizer, an antioxidant, a preservative, a metal ion complexing agent and the like are selected, and the auxiliary materials meeting the requirements are screened out.
As another preferable scheme of the embodiment of the invention, the paint comprises the following components in percentage by mass: 12.5-28 percent of the traditional Chinese medicine composition, 10-20 percent of gel matrix, 5-15 percent of humectant, 3-7 percent of solubilizer, 0.05-0.5 percent of antioxidant, 0.01-0.05 percent of metal ion complexing agent, 0.1-1 percent of preservative and the balance of distilled water, wherein the sum of the mass percentages of the components is 100 percent.
As another preferable scheme of the embodiment of the invention, the nasal gel comprises the following components in percentage by mass: 17.5-22% of the traditional Chinese medicine composition, 14-16% of gel matrix, 8-12% of humectant, 4-6% of solubilizer, 0.1-0.2% of antioxidant, 0.02-0.04% of metal ion complexing agent, 0.3-0.7% of preservative and the balance of distilled water, wherein the sum of the mass percentages of the components is 100%.
Wherein, the selection of the gel matrix comprises the following steps: hydroxypropyl methyl cellulose is an excellent gel matrix, is used as a high polymer material, has the characteristics of high transparency, good stability, strong thickening capability, salt resistance, stable pH, good water retention, stable size, good film forming property, wide enzyme resistance, good dispersibility, strong cohesiveness and the like, and can be used as a good gel matrix; meanwhile, the preparation process is simple, the biocompatibility is good, the irritation is low, and the coating is comfortable.
Selecting a humectant: the glycerin-containing gel has the advantages of minimum water loss rate, best moisturizing effect, small irritation of glycerin and small influence on the gelling temperature, and meets the requirements of preparations. Therefore, glycerin is selected as the gel humectant. The prescription of different glycerol dosage is investigated through experiments, and the appearance and the viscosity are optimal when the glycerol content is 10 percent by comparing the smooth and fine degree and the viscosity of the appearance of the gel;
selection of solubilizer: propylene glycol has low toxicity to nasal cilia and no pungent odor.
Selection of antioxidant: because the gel prepared by the invention is used for nasal administration, and the pH value of the gel is controlled to be between 5.5 and 6.5, the sodium bisulfite is considered to be used as an antioxidant.
Selection of metal ion complexing agent: the nasal secretion contains various metal ions, and the existence of the metal ions can accelerate the oxidation reaction. Although an antioxidant has been added, it is necessary to add disodium edetate complex metal ions to prevent the drug from being oxidized, and also to improve the permeability of the drug.
Selection of a preservative: chlorobutanol is added as a preservative, which has the advantage of producing no or only less irritation of the nasal mucosa and cilia toxicity in the bacteriostatic concentration range.
Selection of pH: the first part of the appendix IX of the Chinese pharmacopoeia 2010 edition has the following provisions: nasal preparations should be nonirritating. The pH value of nasal secretion of normal people is 5.5-6.5, and the pH value of the nasal preparation is kept at 4.5-6.5, so that the pH value can be adjusted to about 6.5 by adding a proper amount of sodium hydroxide.
As another preferable scheme of the embodiment of the present invention, the gel matrix is hydroxypropyl methylcellulose, the humectant is glycerin, the solubilizer is propylene glycol, the antioxidant is sodium bisulfite, the metal ion complexing agent is disodium edetate, and the preservative is chlorobutanol.
Another object of the embodiments of the present invention is to provide a method for preparing the nasal gel, which comprises the following steps:
weighing the traditional Chinese medicine composition, a gel matrix, a humectant, a solubilizer, an antioxidant, a metal ion complexing agent, a preservative and distilled water according to the mass percentage of the components;
mixing the preservative with part of the distilled water to obtain a mixture A;
mixing and grinding the gel matrix and the humectant, and then adding the mixture A for mixing to obtain a mixture B;
mixing the traditional Chinese medicine composition, the solubilizer, the antioxidant and the metal ion complexing agent, and then mixing with the mixture B to obtain a mixture C;
and mixing the mixture C with the rest part of distilled water, and then adjusting the pH value of the mixture C to 6.2-6.8 by using a pH regulator to obtain the nasal gel.
Another object of the embodiments of the present invention is to provide a nasal gel prepared by the above preparation method.
It is a further object of embodiments of the present invention to provide a use of a nasal gel as described above in the manufacture of a medicament for the treatment of migraine.
The traditional Chinese medicine composition for treating migraine provided by the embodiment of the invention has the synergistic and complementary effects of the spina date seeds on the basis of a classical prescription of 'a large ligusticum wallichii prescription' for treating migraine, and the mint is added for inducing resuscitation and promoting penetration, so that the traditional Chinese medicine composition accords with the relevant principle of compatibility of traditional Chinese medicines; the nasal gel prepared from the traditional Chinese medicine composition has small side effect and high safety, is superior to the traditional prescription in the aspects of quickly relieving headache symptoms, relieving duration, stabilizing and reliability in curative effect and the like, can be used for medicine production practice, and is an ideal prescription hopefully replacing the traditional oral preparation. In addition, the nasal gel belongs to nasal mucosa gel, has the characteristics of quick response, long action time and avoidance of liver first-pass effect, has the advantages of longer detention time and higher bioavailability in nasal cavity than nasal drops and sprays, and is more suitable for treating migraine diseases.
Detailed Description
In order to clearly and completely describe the technical solutions in the embodiments of the present invention in combination with the embodiments of the present invention, it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The preparation methods of the ligusticum wallichii extract, the gastrodia elata extract and the spina date seed extract adopted in the following embodiments are respectively as follows:
preparing a gastrodia elata extract: taking 120g of gastrodia elata, adding 16 times of 65% ethanol for reflux extraction, carrying out ethanol extraction for 4 times, carrying out 1.5 hours each time, wherein the extraction rate of gastrodin is 0.983%, combining extracting solutions, selecting AB-8 type macroporous resin, carrying out column loading on the macroporous resin with the concentration of 0.5g/mL, the pH of column loading liquid of 8.0, carrying out maximum sample loading on the macroporous resin with the maximum sample loading amount of 0.7BV, carrying out adsorption flow rate of 2-4 BV/h and the diameter-height ratio of 1:9, eluting with 1BV of distilled water, discarding, then eluting with 10% ethanol, carrying out elution flow rate of 3-8 BV/h, and carrying out purification on the extract with the volume of 6BV of eluent to obtain the gastrodia elata extract.
Preparing a ligusticum wallichii extract: taking 500g of ligusticum wallichii medicinal material, adding 8 times of 80% ethanol, extracting for 3 times, extracting for 2 hours each time, merging filtrate, recovering the ethanol under reduced pressure, concentrating until the mass concentration of the liquid medicine is about 0.5g/mL, centrifuging (4000r/min) for 15min, taking HPD100 type macroporous resin on supernate, eluting by using distilled water until the effluent is colorless, then eluting by using 50% ethanol with 6 times of column volume, collecting the eluate, recovering the ethanol, drying under reduced pressure to obtain the ligusticum wallichii extract ferulic acid, wherein the average yield of the total solid is 2.78%.
Preparing a spina date seed extract: taking 80g of spina date seeds, performing reflux extraction for 3 times by using an ethanol solution with the volume fraction of 8 times and 70% for 2 hours each time, combining filtrates, evaporating the solvent to dryness to prepare a spina date seed ethanol crude extract, enriching and purifying the spina date seed ethanol crude extract by using A B-8 macroporous adsorption resin, performing sample loading and adsorption for 1.5 hours, wherein the sample loading concentration is 20 times of the water addition amount of the extract, the elution flow rate is 1.0mL/min, removing impurities by using the water and the ethanol solution with the volume fraction of 40%, then eluting by using the ethanol solution with the volume fraction of 70% for 160mL, collecting the part of eluent, and performing reduced pressure concentration to dryness to obtain the spina date seed extract. The optimization result shows that the mass fraction of the spina date seed total saponin is 52%, and the measured mass fractions of the spina date seed saponin A and the spina date seed saponin B are 2.298% and 0.789% respectively.
Example 1
This embodiment provides a method for preparing a nasal gel for treating migraine, comprising the steps of:
s1, weighing 10g of ligusticum wallichii extract, 0.5g of gastrodia elata extract, 1g of spina date seed extract, 1g of menthol, 10g of gel matrix, 5g of humectant, 3g of solubilizer, 0.05g of antioxidant, 0.01g of metal ion complexing agent and 0.1g of preservative for later use. Wherein the gel matrix is hydroxypropyl methylcellulose, the humectant is glycerin, the solubilizer is propylene glycol, the antioxidant is sodium bisulfite, the metal ion complexing agent is disodium ethylenediamine tetraacetic acid, and the preservative is chlorobutanol.
S2, mixing the weighed preservative with 10g of distilled water to obtain a mixture A.
S3, mixing, wetting and grinding the weighed gel matrix and humectant, adding the mixture A, mixing, and stirring for a certain time to fully expand to obtain a mixture B.
S4, mixing and dissolving the weighed ligusticum wallichii extract, gastrodia elata extract and spina date seed extract with a solubilizer, mixing with the weighed antioxidant and metal ion complexing agent, and adding the mixture into the mixture B for mixing to obtain a mixture C.
S5, adding distilled water into the mixture C, supplementing to 100g, adding a pH regulator to adjust the pH value to 6.2, and grinding uniformly to obtain the nasal gel.
Example 2
This embodiment provides a method for preparing a nasal gel for treating migraine, comprising the steps of:
s1, weighing 18g of ligusticum wallichii extract, 2g of gastrodia elata extract, 5g of spina date seed extract, 3g of menthol, 20g of gel matrix, 15g of humectant, 7g of solubilizer, 0.5g of antioxidant, 0.05g of metal ion complexing agent and 1g of preservative for later use. Wherein the gel matrix is hydroxypropyl methylcellulose, the humectant is glycerin, the solubilizer is propylene glycol, the antioxidant is sodium bisulfite, the metal ion complexing agent is disodium ethylenediamine tetraacetic acid, and the preservative is chlorobutanol.
S2, mixing the weighed preservative with 10g of distilled water to obtain a mixture A.
S3, mixing, wetting and grinding the weighed gel matrix and humectant, adding the mixture A, mixing, and stirring for a certain time to fully expand to obtain a mixture B.
S4, mixing and dissolving the weighed ligusticum wallichii extract, gastrodia elata extract and spina date seed extract with a solubilizer, mixing with the weighed antioxidant and metal ion complexing agent, and adding the mixture into the mixture B for mixing to obtain a mixture C.
S5, adding distilled water into the mixture C, supplementing to 100g, adding a pH regulator to adjust the pH value to 6.8, and grinding uniformly to obtain the nasal gel.
Example 3
This embodiment provides a method for preparing a nasal gel for treating migraine, comprising the steps of:
s1, weighing 12g of ligusticum wallichii extract, 0.8g of gastrodia elata extract, 2g of spina date seed extract, 2g of menthol, 12g of gel matrix, 12g of humectant, 4g of solubilizer, 0.08g of antioxidant, 0.02g of metal ion complexing agent and 0.2g of preservative for later use. Wherein the gel matrix is hydroxypropyl methylcellulose, the humectant is glycerin, the solubilizer is propylene glycol, the antioxidant is sodium bisulfite, the metal ion complexing agent is disodium ethylenediamine tetraacetic acid, and the preservative is chlorobutanol.
S2, mixing the weighed preservative with 10g of distilled water to obtain a mixture A.
S3, mixing, wetting and grinding the weighed gel matrix and humectant, adding the mixture A, mixing, and stirring for a certain time to fully expand to obtain a mixture B.
S4, mixing and dissolving the weighed ligusticum wallichii extract, gastrodia elata extract and spina date seed extract with a solubilizer, mixing with the weighed antioxidant and metal ion complexing agent, and adding the mixture into the mixture B for mixing to obtain a mixture C.
S5, adding distilled water into the mixture C, supplementing to 100g, adding a pH regulator to adjust the pH value to 6.4, and grinding uniformly to obtain the nasal gel.
Example 4
This embodiment provides a method for preparing a nasal gel for treating migraine, comprising the steps of:
s1, weighing 17g of ligusticum wallichii extract, 1.8g of gastrodia elata extract, 4g of spina date seed extract, 2g of menthol, 10-20 g of gel matrix, 12g of humectant, 4g of solubilizer, 0.4g of antioxidant, 0.04g of metal ion complexing agent and 0.9g of preservative for later use. Wherein the gel matrix is hydroxypropyl methylcellulose, the humectant is glycerin, the solubilizer is propylene glycol, the antioxidant is sodium bisulfite, the metal ion complexing agent is disodium ethylenediamine tetraacetic acid, and the preservative is chlorobutanol.
S2, mixing the weighed preservative with 10g of distilled water to obtain a mixture A.
S3, mixing, wetting and grinding the weighed gel matrix and humectant, adding the mixture A, mixing, and stirring for a certain time to fully expand to obtain a mixture B.
S4, mixing and dissolving the weighed ligusticum wallichii extract, gastrodia elata extract and spina date seed extract with a solubilizer, mixing with the weighed antioxidant and metal ion complexing agent, and adding the mixture into the mixture B for mixing to obtain a mixture C.
S5, adding distilled water into the mixture C, supplementing to 100g, adding a pH regulator to adjust the pH value to 6.6, and grinding uniformly to obtain the nasal gel.
Example 5
This embodiment provides a method for preparing a nasal gel for treating migraine, comprising the steps of:
s1, weighing 13g of ligusticum wallichii extract, 1g of gastrodia elata extract, 2g of spina date seed extract, 1.5g of menthol, 14g of gel matrix, 8g of humectant, 4g of solubilizer, 0.1g of antioxidant, 0.02g of metal ion complexing agent and 0.3g of preservative for later use. Wherein the gel matrix is hydroxypropyl methylcellulose, the humectant is glycerin, the solubilizer is propylene glycol, the antioxidant is sodium bisulfite, the metal ion complexing agent is disodium ethylenediamine tetraacetic acid, and the preservative is chlorobutanol.
S2, mixing the weighed preservative with 10g of distilled water to obtain a mixture A.
S3, mixing, wetting and grinding the weighed gel matrix and humectant, adding the mixture A, mixing, and stirring for a certain time to fully expand to obtain a mixture B.
S4, mixing and dissolving the weighed ligusticum wallichii extract, gastrodia elata extract and spina date seed extract with a solubilizer, mixing with the weighed antioxidant and metal ion complexing agent, and adding the mixture into the mixture B for mixing to obtain a mixture C.
S5, adding distilled water into the mixture C, supplementing to 100g, adding a pH regulator to adjust the pH value to 6.5, and grinding uniformly to obtain the nasal gel.
Example 6
This embodiment provides a method for preparing a nasal gel for treating migraine, comprising the steps of:
s1, weighing 15g of ligusticum wallichii extract, 1.5g of gastrodia elata extract, 3g of spina date seed extract, 2.5g of menthol, 16g of gel matrix, 12g of humectant, 6g of solubilizer, 0.2g of antioxidant, 0.04g of metal ion complexing agent and 0.7g of preservative for later use. Wherein the gel matrix is hydroxypropyl methylcellulose, the humectant is glycerin, the solubilizer is propylene glycol, the antioxidant is sodium bisulfite, the metal ion complexing agent is disodium ethylenediamine tetraacetic acid, and the preservative is chlorobutanol.
S2, mixing the weighed preservative with 10g of distilled water to obtain a mixture A.
S3, mixing, wetting and grinding the weighed gel matrix and humectant, adding the mixture A, mixing, and stirring for a certain time to fully expand to obtain a mixture B.
S4, mixing and dissolving the weighed ligusticum wallichii extract, gastrodia elata extract and spina date seed extract with a solubilizer, mixing with the weighed antioxidant and metal ion complexing agent, and adding the mixture into the mixture B for mixing to obtain a mixture C.
S5, adding distilled water into the mixture C, supplementing to 100g, adding a pH regulator to adjust the pH value to 6.5, and grinding uniformly to obtain the nasal gel.
Example 7
This embodiment provides a method for preparing a nasal gel for treating migraine, comprising the steps of:
s1, weighing 14.2g of ligusticum wallichii extract, 1.3g of gastrodia elata extract, 2.5g of spina date seed extract, 2g of menthol, 15g of gel matrix, 10g of humectant, 5g of solubilizer, 0.15g of antioxidant, 0.03g of metal ion complexing agent and 0.5g of preservative for later use. Wherein the gel matrix is hydroxypropyl methylcellulose, the humectant is glycerin, the solubilizer is propylene glycol, the antioxidant is sodium bisulfite, the metal ion complexing agent is disodium ethylenediamine tetraacetic acid, and the preservative is chlorobutanol.
S2, mixing the weighed preservative with 10g of distilled water to obtain a mixture A.
S3, mixing, wetting and grinding the weighed gel matrix and humectant, adding the mixture A, mixing, and stirring for a certain time to fully expand to obtain a mixture B.
S4, mixing and dissolving the weighed ligusticum wallichii extract, gastrodia elata extract and spina date seed extract with a solubilizer, mixing with the weighed antioxidant and metal ion complexing agent, and adding the mixture into the mixture B for mixing to obtain a mixture C.
S5, adding distilled water into the mixture C, supplementing to 100g, adding a pH regulator to adjust the pH value to 6.5, and grinding uniformly to obtain the nasal gel.
Test example:
firstly, testing toxicity to nasal mucosa cilia:
the toxicity to nasal cilia is an important factor in evaluating nasal delivery systems, as they may have toxic effects on nasal mucosal tissues and nasal cilia. The cilia of the nasal cavity are often affected to varying degrees by nasal administration, and some drugs may even cause irreversible cessation of ciliary movement. Therefore, the research on the influence of the medicine and the auxiliary materials on the nasal cilia is an important basic research in the prescription design of the nasal administration preparation. The in vivo toad palatal model was therefore used to evaluate the effect of "nasal gel prepared as in example 7 above" on ciliary clearance as follows:
1. method of producing a composite material
1.1 Experimental materials
1.1.1 physiological saline: proper amount;
1.1.2 drugs: the nasal gel prepared in example 7 above;
administration dose: calculated as 10 times the oral dose in adult humans: the nasal gel is prepared from rhizoma Ligustici Chuanxiong (60 kg) for adult (weight) by modifying the extract content to 0.2g, and mouse with drug administration dose 10 times of that of adult, and the main drug concentration of the gel is 0.2, and the nasal gel for mouse needs 165mg/kg is calculated.
1.2 Experimental animals
The weight of the Bufo bufo gargarizans Cantor (purchased by oneself) is 70-80 g, and the weight is half of that of male and female.
1.3 Experimental methods
Selecting and lying on the back and fixing the bufo gargarizans, opening the oral cavity by using hemostatic forceps, dripping 0.5mL of the bufo gargarizans into the mucous membrane of the upper jaw to completely immerse the mucous membrane of the upper jaw, washing the mucous membrane of the upper jaw by using physiological saline after contacting for 1h, then separating the mucous membrane of the upper jaw by using surgical scissors, washing the mucous membrane by using the physiological saline, flatly paving the mucous membrane on a glass slide with the upward side facing to the upper surface, dripping the physiological saline, covering a cover glass, and observing the movement condition of cilia under an optical microscope of 40 multiplied by 10. And after the observation is finished, placing the glass slide into a chromatographic cylinder added with a small amount of distilled water, sealing, and enabling the water vapor in the cylinder to be nearly saturated at the temperature of 20-25 ℃. The slides were removed at intervals until ciliary beat ceased, and the time from washing the test specimens until ciliary beat ceased was recorded. The negative control group was saline 0.5mL, and the relative percentage was calculated as "relative percentage (%) (average duration of oscillation of sample/average duration of oscillation of control group) × 100", and the higher the percentage, the lower the toxicity of the test sample to cilia.
The results of the above experiments are shown in table 1.
TABLE 1 nasal gel effect on ciliary movement time (n ═ 3)
Note: comparison with negative control group
The results show that: control group: the cilia are clear and regular in shape, do not fall off and regularly swing; administration group: cilia are clear in morphology, somewhat disorganized, with slightly reduced wobble, with a percentage of 96.3% compared to the negative control group. The nasal gel has certain influence on ciliary movement, but has low toxicity and almost no influence on normal physiological functions of the nasal cavity.
Second, pharmacodynamics research experiment
1.1 Experimental materials
1.1.1 physiological saline: proper amount;
1.1.2 drugs: the nasal gel prepared in example 7 above;
administration dose: calculated as 10 times the oral dose in adult humans: the nasal gel is prepared by taking the extract content of the ligusticum wallichii prescription nasal gel which needs to be improved by an adult (the weight: 60kg) as 0.2g (referring to the determination of the content of the main drug), the administration dose of a mouse is generally about 10 times of the administration dose of the adult, the concentration of the main drug of the gel is 0.2, and the requirement of 165mg/kg of the nasal gel for the mouse is calculated.
1.1.3 improved Dachuanxiong prescription liquid medicine: in example 7, the main drugs (rhizoma Chuanxiong extract, rhizoma Gastrodiae extract, semen Ziziphi Spinosae extract, and menthol) are added with distilled water to obtain 100mL medicinal liquid;
administration dose: calculated as 10 times the oral dose in adult humans: the method comprises the steps of setting the content of the extract in the formula of the rhizoma ligustici wallichii which needs to be improved for an adult (the weight: 60kg) as 1g (referring to the determination of the content of the main drug), generally setting the administration dose of a mouse to be about 10 times of the administration dose of the adult, setting the concentration of the main drug of the liquid medicine to be 0.2, and calculating that the mouse needs 850mg/kg of the liquid medicine of the rhizoma ligustici wallichii which needs to be improved.
1.2 Experimental animals
Healthy Kunming mice are half male and half female, and have the weight of 18-25 g.
2. Method of producing a composite material
2.1 Experimental methods
2.1.2 acetic acid writhing method
50 mice were randomly divided into 5 groups of 10 each, weighed and numbered. Group A is normal saline control group, and appropriate amount of normal saline is administered into nasal cavity, and acetic acid solution is injected into abdominal cavity after 5 min; the group B is oral control group, and is administered by intragastric administration of 850mg/kg (body weight) of the improved rhizoma Ligustici Chuanxiong formula liquid medicine, and 30min after administration, intraperitoneal injection of acetic acid solution is performed; the nasal administration (nasal gel) was carried out in C, D, E groups of low, medium and high doses, at 82.5mg/kg, 165mg/kg and 330mg/kg, respectively, and the administration was carried out 5min before the abdominal injection with the acetic acid solution. Each mouse was injected intraperitoneally with 0.6% acetic acid solution (0.1 mL).
2.1.3 Hot plate method
Selecting 50 mice with pain reaction on a hot plate at 50 ℃ for 5-30 s, randomly dividing the mice into 5 groups, wherein each group comprises 10 mice, the group A is a normal saline control group, and the nasal cavity is provided with normal saline; the group B is oral control group, and 850mg/kg (weight) of improved rhizoma Ligustici Chuanxiong formula liquid medicine is administered by intragastric administration; the nasal administration (nasal gel) was carried out in C, D, E groups of low, medium and high doses, which were 82.5mg/kg, 165mg/kg and 330mg/kg, respectively.
2.2 Observation index and measurement method
2.2.1 acetic acid writhing method
Observing and recording the time of writhing after acetic acid solution injection and the times of writhing reaction within 20min, and calculating the analgesic rate according to the following formula:
2.2.2 Hot plate method
The pain response latency was measured before and 15min, 30min, 60min, 90min after administration to each mouse, and the pain threshold increase rate was calculated according to the following formula:
2.3 data processing
Comparisons between observations between groups were analyzed by One-way ANOVA and data were processed using Spss22 software.
3. Test results
3.1 acetic acid writhing method
The time of writhing, the times of writhing within 20min and the pain-relieving rate of each group of animals are shown in table 2.
TABLE 2 Effect of nasal gel on mouse acetic writhing response (, (
n＝10)
Note: p compared to control group<0.05，**P<0.01; in comparison with the group B,#P<0.05，##P<0.01; in comparison with the group E,△P<0.05，△△P<0.01。
from the results in table 2, each administration group had significant difference (P <0.01) compared with the blank group in terms of the number of writhing of the mice, which indicates that each treatment group significantly reduced the pain response of the mice; compared with the group B, the group C (low dose) has no significant difference (P > O.05), while the group D (medium dose) and the group E (high dose) have significant difference (P <0.01), which shows that the analgesic effect of the nasal administration is enhanced compared with the analgesic effect of the oral administration under the condition of the same dose; compared with the E (high dose) group, P <0.01 in the C (low dose) group and P <0.05 in the D (medium dose) group both suggested significant differences, indicating that the analgesic effect of the test samples increased with increasing dose. The calculated results of analgesic rate were about 19.8% higher in group D and about 37.6% higher in group E compared to group B.
3.2 Hot plate method
The pain threshold and the pain threshold increase rate before and after administration of the drug to each group of animals are shown in Table 3.
TABLE 3 Effect of nasal gel on Hot plate-induced pain response in mice (n ═ 10)
Note: compared with the control group, the compound of the formula,*P<0.05，**P<0.01; in comparison with the group B,#P<0.05，##P<0.01; in comparison with the group E,△P<0.05，△△P<0.01。
as can be seen from table 3, the pain threshold increases at each time point of each administration group were significantly different from those of the blank control group (P <0.05 in group B and P <0.01 in group C, D, E), which indicates that the pain of the mice in each administration group was effectively inhibited; compared with the treatment group of the group B, the pain threshold increasing rate of each time point of the treatment group of the test sample is obviously different (P <0.01), which indicates that the analgesic effect of the test sample on the mice is higher than that of the B; compared with the group E, the pain threshold increase rate of each time point of the group C and the group D is obviously different (P is less than 0.01), which shows that the curative effect of the medicine is enhanced along with the increase of the dosage. The pain threshold increasing rate of the groups C, D and E increases with time at the beginning, and the pain threshold is basically maintained at a level with time extension when 30min is reached; the increase rate of the pain threshold of the B group is slow along with the increase rate of the pain threshold of the B group, which also indicates that the speed of the active ingredients entering the systemic circulation is higher after the nasal administration of the nasal gel provided by the invention than the oral administration.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (10)
1. The traditional Chinese medicine composition for treating migraine is characterized by comprising the following components in parts by weight: 10-18 parts of ligusticum wallichii extract, 0.5-2 parts of gastrodia elata extract, 1-5 parts of spina date seed extract and 1-3 parts of menthol.
2. The traditional Chinese medicine composition for treating migraine according to claim 1, wherein the traditional Chinese medicine composition comprises the following components in parts by weight: 13-15 parts of ligusticum wallichii extract, 1-1.5 parts of gastrodia elata extract, 2-3 parts of spina date seed extract and 1.5-2.5 parts of menthol.
3. The traditional Chinese medicine composition for treating migraine according to claim 1 or 2, wherein the ligusticum wallichii extract, the gastrodia elata extract and the spina date seed extract are all ethanol extracts.
4. A nasal gel comprising the Chinese medicinal composition of any one of claims 1-3.
5. The nasal gel according to claim 4, characterized by comprising the following components in percentage by mass: the traditional Chinese medicine composition comprises, by mass, 12.5-28% of a traditional Chinese medicine composition, 10-20% of a gel matrix, 5-15% of a humectant, 3-7% of a solubilizer, 0.05-0.5% of an antioxidant, 0.01-0.05% of a metal ion complexing agent, 0.1-1% of a preservative and the balance of distilled water, wherein the sum of the mass percentages of the components is 100%.
6. The nasal gel according to claim 5, characterized by comprising the following components in percentage by mass: 17.5-22% of the traditional Chinese medicine composition, 14-16% of a gel matrix, 8-12% of a humectant, 4-6% of a solubilizer, 0.1-0.2% of an antioxidant, 0.02-0.04% of a metal ion complexing agent, 0.3-0.7% of a preservative and the balance of distilled water, wherein the sum of the mass percentages of the components is 100%.
7. A nasal gel according to claim 5 wherein the gel base is hydroxypropyl methylcellulose, the humectant is glycerol, the solubilizer is propylene glycol, the antioxidant is sodium bisulfite, the metal ion complexing agent is disodium edetate and the preservative is chlorobutanol.
8. A method of preparing a nasal gel according to any of claims 4 to 7 comprising the steps of:
weighing the traditional Chinese medicine composition, a gel matrix, a humectant, a solubilizer, an antioxidant, a metal ion complexing agent, a preservative and distilled water according to the mass percentage of the components;
mixing the preservative with part of the distilled water to obtain a mixture A;
mixing and grinding the gel matrix and the humectant, and then adding the mixture A for mixing to obtain a mixture B;
mixing the traditional Chinese medicine composition, the solubilizer, the antioxidant and the metal ion complexing agent, and then mixing with the mixture B to obtain a mixture C;
and mixing the mixture C with the rest part of distilled water, and then adjusting the pH value of the mixture C to 6.2-6.8 by using a pH regulator to obtain the nasal gel.
9. A nasal gel prepared by the method of claim 8.
10. Use of a nasal gel according to any one of claims 4 to 7 or 9 in the manufacture of a medicament for the treatment of migraine.
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