CN116327759A - Composition containing butylphthalide, edaravone and borneol and compound soft capsule - Google Patents
Composition containing butylphthalide, edaravone and borneol and compound soft capsule Download PDFInfo
- Publication number
- CN116327759A CN116327759A CN202111589166.8A CN202111589166A CN116327759A CN 116327759 A CN116327759 A CN 116327759A CN 202111589166 A CN202111589166 A CN 202111589166A CN 116327759 A CN116327759 A CN 116327759A
- Authority
- CN
- China
- Prior art keywords
- parts
- edaravone
- butylphthalide
- soft capsule
- borneol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- HJXMNVQARNZTEE-UHFFFAOYSA-N Butylphthalide Chemical compound C1=CC=C2C(CCCC)OC(=O)C2=C1 HJXMNVQARNZTEE-UHFFFAOYSA-N 0.000 title claims abstract description 180
- 239000007901 soft capsule Substances 0.000 title claims abstract description 114
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 title claims abstract description 107
- 229950009041 edaravone Drugs 0.000 title claims abstract description 105
- 229950005197 butylphthalide Drugs 0.000 title claims abstract description 90
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 title claims abstract description 75
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 229940116229 borneol Drugs 0.000 title claims abstract description 68
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 title claims abstract description 68
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 title claims abstract description 68
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Abstract
The invention discloses a composition containing butylphthalide, edaravone and borneol, a compound soft capsule and a preparation method thereof, and belongs to the technical field of medicines. The invention provides a pharmaceutical composition, which comprises the following components in percentage by mass: 0.5-10:0.1-10 parts of butylphthalide, edaravone and borneol. The addition of borneol can improve the blood brain barrier permeation effect of butylphthalide and edaravone in the brain, and simultaneously the three components play a synergistic effect to improve the drug effect. In addition, the invention quantitatively presses and encapsulates the oil substance butylphthalide and the edaravone with low water solubility and other functional substances in the adhesive film to form the sealed capsules with different sizes and shapes, which can be used for improving the symptoms of patients with brain diseases, and can play a synergistic effect and improve the curative effect.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a composition containing butylphthalide, edaravone and borneol, a compound soft capsule and a preparation method thereof.
Background
The butylphthalide commonly called apigenin A is a main component of celery volatile oil, can be extracted from natural celery seed oil, and can also be obtained through chemical synthesis, and the chemical structural formula is as follows:
Proved by researches, the butylphthalide is used for treating light and moderate acute ischemic cerebral apoplexy, has stronger anti-cerebral ischemia effect, obviously improves microcirculation and blood flow of ischemic brain areas and increases the number of capillary vessels of the ischemic areas; relieving cerebral edema, and reducing the infarct area of rat ischemia; improving cerebral energy metabolism and microcirculation and blood flow of ischemic brain region, inhibiting nerve cell apoptosis, and resisting cerebral thrombosis and platelet aggregation. For example, chinese patent No. 98125618.X discloses the use of L-butylcatechol (L-butylphthalide) in antithrombotic and antiplatelet aggregation drugs, indicating that butylcatechol has the function of regulating the NOS-NO-cGMP system and the metabolism of arachidonic acid by nerve cells after cerebral ischemia; chinese patent 93117148.2 discloses the use of apigenin A in the manufacture of a medicament for the prophylaxis and treatment of diseases caused by cerebral ischemia in mammals and humans.
Edaravone is a brain protecting agent, can remove free radicals, inhibit lipid peroxidation, inhibit oxidative damage of brain cells, vascular endothelial cells and nerve cells, and is used for treating neuropathy caused by cerebral infarction, relieving cerebral edema and brain damage, saving dying delayed neurons and avoiding further damage of the central nervous system. In addition to these effects, edaravone however, also exhibits beneficial effects in inflammation, matrix metalloproteinases, nitric oxide production and apoptosis. It is expected to have the same activity as phenols because it shows similar antioxidant and radical scavenging effects due to its aromatic hydroxyl groups. Edaravone can be divided into three different tautomeric forms: amine, ketone and enol forms, aromatic hydroxy groups are produced by keto-enol tautomerism. However, in contrast to phenols, edaravone has no toxic effect, which is also one of the reasons why edaravone is superior to phenols. The chemical structural formula is as follows:
Approximately 50% of the edaravone molecules are ionized and present in anionic form at physiological pH. The anionic form of edaravone is also a more reactive form, which reacts readily with ROS in the brain, producing an antioxidant effect. The advantage of edaravone over idebenone, baicalein, catechin (flavonol) and other free radical scavengers is that blood brain barrier penetration is not a major obstacle, as edaravone is a low molecular weight lipophilic molecule with solubility in both water and lipids. Thus, it can easily cross the blood brain barrier and act on target sites in the brain. It is estimated that the relative proportion of edaravone plasma to cerebrospinal fluid levels is between 50% and 65%.
In the clinical study of Zhu Yuanqun et al, the results of the combination of the soft capsule of the butylphthalide and the edaravone for treating acute cerebral infarction (30 mg of the edaravone is used for intravenous drip for 2 times per day, and 200mg of the soft capsule of the butylphthalide is taken orally for 3 times per day, and 14 days is a treatment course) show that the combination of the butylphthalide and the edaravone for treating acute cerebral infarction can effectively improve the nerve function of a patient, accelerate the recovery of the daily life ability, improve the treatment effective rate of the cerebral infarction and have good synergistic effect on improving the symptoms of the patient with the acute cerebral infarction.
However, butylphthalide is a yellow oily liquid, insoluble in water, has low oral bioavailability in humans, whereas edaravone is a white powder, has poor water solubility, poor permeability, poor bioavailability, poor water stability, short half-life, and some side effects such as hepatotoxicity and nephrotoxicity may be major obstacles in preparing oral formulations.
Borneol, also called borneol, orange slices, borneol incense, plum blossom borneol, corm bromoxynil, plum blossom borneol, plum blossom ice and the like, is a crystal obtained by extracting resin and volatile oil processed products of borneol incense family plants, and is almost pure dextrorotatory borneol. Also useful are chemical syntheses. The borneol has the following effects: pain and corrosion resistance, borneol is used for local part, and has little irritation to sensory nerve endings. Experiments prove that the product has certain analgesic and mild antiseptic effects; antibacterial, which can inhibit the growth of vibrio cholerae, escherichia coli and staphylococcus aureus in a test tube; inducing resuscitation and refreshing mind, borneol is bitter in flavor and enters heart meridian, so it is fragrant in smell, spicy and fleeting, and avoiding bad smell. Unblocking nine orifices. Enters heart meridian, and heart governs the sense of mind, so called monarch organ, so it can induce resuscitation with fragrance to refresh mind. "Su Wen-Ling lan Mi Dian Lun" is: "heart person: the principal sense of mind is to be clear. ", it is cold in nature and clear heat, pungent and bitter in nature and discharges. So it can be used for treating apoplexy, phlegm syncope, and mental confusion caused by high fever; clearing heat, relieving pain and promoting tissue regeneration. It has effects of dispelling cold and clearing heat, and has effects of clearing heat and relieving pain, relieving itching and promoting granulation. It is pungent and fragrant, and can reach viscera, and can dispel wind-damp and dispel heat by bitter action due to nine orifices of the viscera and Bo Tong. "Bencaojing Shu" carries: borneol ' all rheumatism is dispersed ', so pathogenic qi in the heart and abdomen is dominant, and rheumatism accumulates '; the action of treating coma, convulsion and borneol inducing resuscitation is similar to musk, but the action is slightly weaker, so it is often combined with the two herbs. Clinically, it is mainly used for treating internal closure symptoms such as syncope of warm diseases and mental syncope, apoplexy, qi syncope, aversion to the middle-jiao, apoplexy and syncope. The product is used for treating sores, scabies, aphtha, sore throat, eye diseases and other diseases by external application, has the effects of detumescence and acesodyne, and has the effects of antisepsis and antipruritic, is mainly used for external application, and can treat the symptoms of gum swelling and pain, sore throat, aphtha and the like by being matched with borax and sodium sulfate; if the nose is plugged and the nasal discharge is caused, a small amount of borneol and boron powder is used for blowing the nose, so that the nose plug can be realized; other external formulas such as traditional Chinese medicine surgery, laryngeal department, wound department, ophthalmology and the like are mostly matched with the product; in addition, it can be used for conjunctival congestion with swelling and pain, sore throat, aphtha, sore and ulcer, and unhealed after ulcer.
The applicant has found that the addition of borneol is favorable for improving the blood brain barrier permeation effect of butylphthalide and edaravone in the brain, and the three can play a synergistic effect at the same time, so that the drug effect is improved. On the other hand, the invention quantitatively presses and encapsulates the oil substance butylphthalide and the edaravone with low water solubility and other functional substances in the adhesive film to form sealed capsules with different sizes and shapes, which can be used for improving the symptoms of patients with brain diseases, and can play a synergistic effect and improve the curative effect. The composition and the compound soft capsule containing the butylphthalide, the edaravone and the borneol are applied to the treatment of the progressive freezing disease and other neurodegenerative diseases, such as MS (multiple sclerosis), AD (Alzheimer disease), PD (Parkinson disease), cerebral apoplexy and the like.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, provides a composition with synergistic brain disease resistance and comprising butylphthalide, edaravone and borneol, and further provides a compound soft capsule comprising butylphthalide, edaravone and borneol and a preparation method thereof. Through screening proper pharmaceutical excipients, the oily substance butylphthalide and edaravone with low water solubility and other functional substances are quantitatively pressed and encapsulated in an adhesive film to form sealed capsules with different sizes and shapes, so that the stability of the edaravone is maintained, the problems of low bioavailability, poor permeability and the like of butylphthalide and edaravone in the prior art when the butylphthalide and edaravone are used for oral administration are overcome, and the blood brain barrier permeation effect of the butylphthalide and the edaravone in the brain is improved by adding borneol, so that the drug effect is further improved, and the symptoms of brain disease patients are improved.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
in one aspect, the invention provides a pharmaceutical composition comprising the following components in percentage by mass: 0.5-10:0.1-10 parts of butylphthalide, edaravone and borneol.
The term "butylphthalide" as used herein includes butylphthalide of the formula or any pharmaceutically acceptable salt, prodrug, metabolite, ester, ether, hydrate, polymorph, solvate, complex and adduct thereof, that is, capable of providing (directly or indirectly) the parent compound upon administration to a subject.
The term "edaravone" as used herein includes references to and includes edaravone of the formula or any pharmaceutically acceptable salt, prodrug, metabolite, ester, ether, hydrate, polymorph, solvate, complex and adduct thereof, i.e. capable of providing (directly or indirectly) the parent compound upon administration to a subject.
The term "borneol" as used herein includes reference to and includes edaravone of the formula or any pharmaceutically acceptable salt, prodrug, metabolite, ester, ether, hydrate, polymorph, solvate, complex and adduct thereof, i.e. capable of providing (directly or indirectly) the parent compound upon administration to a subject.
Preferably, the butylphthalide is a racemate, a levorotatory body or a dextrorotatory body.
Preferably, the pharmaceutical composition comprises the following components in percentage by mass of 10-25:1-6:1-5 parts of butylphthalide, edaravone and borneol.
Further preferably, the pharmaceutical composition comprises the components with the mass ratio of 15-25:3-6:2-5 parts of butylphthalide, edaravone and borneol.
Further preferably, the pharmaceutical composition comprises the components in a mass ratio of 20:4:3, butylphthalide, edaravone and borneol.
In yet another aspect, the present invention provides a soft capsule medical fluid comprising the above pharmaceutical composition and one or more pharmaceutically acceptable additives and/or excipients.
Non-limiting examples of the term "pharmaceutically acceptable additives and/or excipients" as used herein include oil phases, emulsifiers, co-emulsifiers, stabilizers, dispersants, and the like.
The soft capsule liquid medicine of the invention can comprise one or more oil phases, wherein the oil phases can be selected from soybean oil, peanut oil, olive oil, corn oil, sesame oil, sunflower seed oil, propylene glycol monocaprylate (CapryolTM PGMC), propylene glycol monocaprylate (CapryolTM 90) and oleic acid polyethylene glycol glyceride [ ]
M2115), propylene glycol monolaurate (Laurogol (TM) 90), glycerol monocaprylate (/ -for) >
MCM C8//>
MCM EP and propylene glycol monocaprylate
PG 8), propylene glycol monolaurate (++>
PG 12), and the like.
The soft capsule medical solution of the invention can comprise one or more emulsifying agents, wherein the emulsifying agents are selected from caprylic capric acid polyethylene glycol glyceride
Polyoxyethylene hydrogenated castor oil (++>
RH40 and hydrogenated castor oil polyoxyethylene ether
RH 40), polyethylene glycol 1000 vitamin E succinate, triethanolamine, glycerol, polysorbate 20, and the like.
The soft capsule medical fluid of the present invention may include one or more co-emulsifiers selected from diethylene glycol monoethyl ether (Transcutol)
) Ethanol, polyethylene glycol 300, and the like.
The soft capsule medical solution of the present invention may include one or more stabilizers selected from sodium sulfite, sodium metabisulfite, cysteine, methionine, dibutylcarboxytoluene, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, ethylenediamine tetraacetic acid, and the like.
The soft capsule medical solution of the present invention may comprise one or more dispersing agents selected from the group consisting of polyethylene glycol PEG-400, polyethylene glycol PEG-600, hydrogenated soybean oil, yellow wax, short chain vegetable oil, and the like.
Preferably, the pharmaceutically acceptable carrier or excipient is an oil phase, an emulsifier, a co-emulsifier and a stabilizer.
Further preferably, the soft capsule liquid medicine comprises 5-30 parts of butylphthalide, 0.5-10 parts of edaravone, 0.1-10 parts of borneol, 20-50 parts of oil phase, 20-50 parts of emulsifying agent, 5-25 parts of auxiliary emulsifying agent and 0.01-5 parts of stabilizing agent.
The term "parts" as used herein refers to parts by weight, representing the relative weight content of the ingredients.
Still more preferably, the soft capsule liquid medicine comprises 15-25 parts of butylphthalide, 3-6 parts of edaravone, 2-5 parts of borneol, 20-25 parts of oil phase, 35-45 parts of emulsifying agent, 15-20 parts of auxiliary emulsifying agent and 0.1-2 parts of stabilizing agent.
Preferably, the oil phase is at least one of propylene glycol monocaprate and corn oil, and more preferably propylene glycol monocaprate.
Preferably, the emulsifier is at least one of propylene glycol monocaprate, polyoxyethylene ether hydrogenated castor oil and polyethylene glycol 1000 vitamin E succinate. Further preferably, the emulsifier is propylene glycol monocaprate and polyoxyethylene ether hydrogenated castor oil, and the weight ratio of the emulsifier to the polyoxyethylene ether hydrogenated castor oil is 1: 1.
Preferably, the co-emulsifier is diethylene glycol monoethyl ether.
Preferably, the stabilizer is at least one of sodium sulfite, L-cysteine hydrochloride and polyethylene glycol. The edaravone used as a main medicine component in the invention is easily oxidized by dissolved oxygen in liquid, and the applicant finds that the effect is better when a specific mixed stabilizer is added, so that the most preferable stabilizer is prepared by the following components in mass ratio of 3:1 sodium sulfite and L-cysteine hydrochloride.
In still another aspect, the invention provides a compound soft capsule, which comprises the soft capsule liquid medicine and a capsule wall material.
The prescription of the capsule wall material comprises sizing material, plasticizer, water and additive.
The capsules of the present invention may comprise one or more sizes which may be selected from gelatin, modified gelatin, carrageenan, modified starch, polyvinyl alcohol, gum arabic and the like.
The capsules of the present invention may include one or more plasticizers, which may be selected from glycerol, xylitol, sorbitol, hydrogenated corn steep liquor, and the like.
The capsules of the present invention may include one or more additional agents which may be selected from antioxidants, disintegrants, colorants, opacifiers, surfactants, flavoring agents, preservatives, and the like.
Such disintegrants include, but are not limited to, PEG-400, cyclodextrin, sorbitol, sorbitan, and the like.
The colorants include, but are not limited to, colored capsules, curcumin, and the like.
The opacifying agent includes, but is not limited to, iron oxide, titanium dioxide, and the like.
The surfactant includes, but is not limited to, tween, span, etc.
Such suspending agents include, but are not limited to, beeswax, but aluminum stearate, ethylcellulose, and the like.
Such flavoring agents include, but are not limited to, sucrose, sorbitol, and the like.
Such preservatives include, but are not limited to, methyl parahydroxybenzoate, propyl parahydroxybenzoate, methyl paraben, ethyl paraben, and the like.
Preferably, the sizing material is selected from at least one of gelatin and acacia.
Preferably, the plasticizer is at least one selected from glycerin and sorbitol.
Preferably, the opacifier is at least one selected from the group consisting of iron trioxide and titanium dioxide.
Preferably, the flavoring agent is selected from sorbitol.
Preferably, the preservative is at least one selected from methyl paraben and ethyl paraben.
As a preferred embodiment, the capsule wall material comprises pharmaceutically acceptable gelatin, acacia, glycerin, sorbitol, iron trioxide, titanium dioxide, methyl paraben, ethyl paraben, sorbitol and purified water.
In still another aspect, the present invention provides a method for preparing the above compound soft capsule. The method comprises the following steps:
(1) Preparing a liquid medicine: adding butylphthalide, edaravone and borneol into the mixture of oil phase, emulsifier, auxiliary emulsifier and stabilizer, heating and stirring to dissolve the medicine uniformly, and cooling to room temperature to obtain liquid medicine;
(2) Preparing a capsule liquid: adding capsule wall material formula components into purified water to obtain capsule liquid;
(3) Pressing soft capsules: and (3) filling the prepared medicinal oil liquid and capsule liquid into an automatic rotary capsule rolling machine, and pressing to obtain the soft capsules.
Preferably, in the step (1), the temperature of the heating and stirring is 15-60 ℃. The purpose of heating is to promote the dissolution uniformity, and the dissolution uniformity can be realized by stirring without heating, and considering the operation time, the heating is preferably performed, and the stirring temperature is not particularly limited and has no obvious influence on the technical effect of the application.
The capsule liquid prepared in the step (2) is prepared by a preparation method conventional in the art, and as a specific preparation mode of the application, the following method can be exemplified:
and (3) taking the sizing material, adding a proper amount of water to enable the sizing material to absorb water and expand to obtain a sizing solution, heating other formulas and water in a sol pot, uniformly mixing, adding the sizing solution, stirring, and standing to obtain the capsule liquid.
Preferably, in step (3), the pressing conditions are: pressing at ventilation place in drying room with temperature of 20-55deg.C.
The composition and the compound soft capsule containing the butylphthalide, the edaravone and the borneol are applied to the treatment of the progressive freezing disease and other neurodegenerative diseases, such as MS (multiple sclerosis), AD (Alzheimer disease), PD (Parkinson disease), cerebral apoplexy and the like.
The beneficial effects of the invention are as follows:
(1) The invention provides a composition with active ingredients of butylphthalide, edaravone and borneol, which can improve symptoms of brain disease patients, play a synergistic role and improve curative effect;
(2) The invention solves the problems of low bioavailability, poor permeability and the like when the butylphthalide and the edaravone are used for oral administration in the prior art, and the borneol is added to improve the blood brain barrier permeation effect of the butylphthalide and the edaravone in the brain, so as to further improve the drug effect;
(3) The invention provides a compound soft capsule for oral administration, which is characterized in that an oil substance butylphthalide, edaravone with low water solubility and other functional substances are quantitatively pressed and encapsulated in a glue film by screening proper medicinal auxiliary materials to form sealed capsules with different sizes and shapes, so that the capsule is used for improving symptoms of patients with brain diseases and keeping the stability of the edaravone.
Drawings
FIG. 1 is a graph showing the particle size of the compound soft capsule of example 4.
Fig. 2 is a potential size diagram of the compound soft capsule of example 4.
FIG. 3 is an HPLC chromatogram of a butylphthalide control.
Fig. 4 is an HPLC profile of butylphthalide in the compound soft capsule of example 4.
Fig. 5 is an HPLC profile of edaravone control.
Fig. 6 is an HPLC profile of edaravone in the compound soft capsule of example 4.
FIG. 7 is a graph of the transendothelial resistance measurement of the blood brain barrier model of example 4.
Fig. 8 is a graph showing the results of measuring transport efficiency of butylphthalide across the blood brain barrier model in the compound soft capsules of example 4 and comparative example 1.
Fig. 9 is a graph showing the results of measuring the transport efficiency of edaravone across the blood brain barrier model in the compound soft capsules of example 4 and comparative example 1.
Fig. 10 is a graph showing comparison of the results of the behavioral changes of each group after administration of the model animals for progressive freezing syndrome.
Detailed Description
The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the invention and are not intended to limit the invention in any way. The following is merely exemplary of the scope of the claimed invention and one skilled in the art can make various changes and modifications to the invention of the present application in light of the disclosure, which should also fall within the scope of the claimed invention.
The invention is further illustrated by means of the following specific examples. The various chemical reagents used in the examples of the present invention were obtained by conventional commercial means unless otherwise specified.
1. Material preparation:
1.1 preparation of medical fluid Material
Butylphthalide, purchased from Chinese food and drug testing institute manufacturer, model 101035-201903;
edaravone, purchased from
(MedChemexpress) manufacturer, model Cat. No.: HY-B0099;CAS No.：89-25-8；
borneol, available from aladine, cat No.: (aladin) B119291;
propylene glycol monocaprate, available from the French Jia Fara lion, lot: 182246;
polyoxyethylene ether hydrogenated castor oil, available from BASF SE, lot number: 12566375L0;
diethylene glycol monoethyl ether, available from French Jia Farfari under the CAS number 111-90-0;
polyethylene glycol glyceride octanoate, shanghai New platinum chemical technology Co., ltd., product number: SAA0077;
sodium sulfite, available from aladine under the model number (aladin) S112300;
l-cysteine hydrochloride (anhydrate), available from CHEMBEE (available from Shanghai dary Fine chemical Co., ltd.), product code: 52-89-1;
corn oil, available from innochem under the model number KYEK851;
polyethylene glycol, available from ACROS under model a0404869;
automatic rotary bag rolling machine, manufacturer's Beijing Zhongtianhui technology Co., ltd, model ZTHT-125.
1.2 preparation of a capsule wall material:
gelatin: purchased from aladine, cat No.: g108396;
glycerol: purchased from Innochem, cat No.: g1100;
methyl paraben: purchased from Innochem, cat No.: a86586;
ethylparaben: purchased from Innochem, cat No.: a87092;
liquid chromatograph: manufacturer Agilent model 1200;
laser particle size analyzer: manufacturer PSS company, NICOMPTM380ZLS model;
human brain microvascular endothelial cell line HBMEC was purchased from basic institute of China medical sciences.
2. Preparation of compound soft capsule
Example 1
Prescription of soft capsule liquid medicine:
20 parts of butylphthalide;
3.5 parts of edaravone;
3 parts of borneol;
20 parts of propylene glycol monocaprate;
38 parts of a mixture of propylene glycol monocaprate and polyoxyethylene ether hydrogenated castor oil (the weight ratio of the propylene glycol monocaprate to the polyoxyethylene ether hydrogenated castor oil is 1:1);
15.3 parts of diethylene glycol monoethyl ether;
sodium sulfite 0.2 parts.
The compound soft capsule is prepared according to the following steps:
(1) Preparing a liquid medicine: adding prescribed amount of butylphthalide, edaravone and Borneolum Syntheticum into mixture of prescribed amount of oil phase, emulsifier, auxiliary emulsifier and stabilizer, heating (35-40deg.C), stirring to dissolve the medicine uniformly, and cooling to room temperature to obtain medicinal liquid (lipid emulsion);
(2) Preparing a capsule liquid: about 150g of gelatin was taken and water was added to the mixture to expand the mixture. Heating 50g of glycerol, 300mg of methylparaben and 150g of water to 60-80 ℃ in a sol pot, uniformly mixing, adding gelatin liquid, stirring, and standing to obtain capsule liquid;
(3) Pressing soft capsules: the prepared medicinal oil liquid and capsule liquid are filled into an automatic rotary capsule rolling machine, and soft capsules are pressed at the ventilation position in a drying chamber with the temperature of 35-55 ℃.
Example 2
Prescription of soft capsule liquid medicine:
10 parts of butylphthalide;
1 part of edaravone;
1 part of borneol;
30 parts of corn oil;
37.7 parts of a mixture of propylene glycol monocaprate and polyoxyethylene ether hydrogenated castor oil (the weight ratio of the propylene glycol monocaprate to the polyoxyethylene ether hydrogenated castor oil is 1:1);
20 parts of diethylene glycol monoethyl ether;
0.3 parts of polyethylene glycol.
The compound soft capsule is prepared according to the following steps:
(1) Preparing a liquid medicine: adding prescribed amount of butylphthalide, edaravone and Borneolum Syntheticum into mixture of prescribed amount of oil phase, emulsifier, auxiliary emulsifier and stabilizer, heating (35-40deg.C), stirring to dissolve the medicine uniformly, and cooling to room temperature to obtain medicinal liquid (lipid emulsion);
(2) Preparing a capsule liquid: about 150g of gelatin was taken and water was added to the mixture to expand the mixture. Heating 50g of glycerol, 300mg of methylparaben and 150g of water to 60-80 ℃ in a sol pot, uniformly mixing, adding gelatin liquid, stirring, and standing to obtain capsule liquid;
(3) Pressing soft capsules: the prepared medicinal oil liquid and capsule liquid are filled into an automatic rotary capsule rolling machine, and soft capsules are pressed at the ventilation position in a drying chamber with the temperature of 35-55 ℃.
Example 3
Prescription of soft capsule liquid medicine:
22 parts of butylphthalide;
3.7 parts of edaravone;
2.5 parts of borneol;
20 parts of propylene glycol monocaprate;
37 parts of a mixture of propylene glycol monocaprate, polyoxyethylene ether hydrogenated castor oil and polyethylene glycol 1000 vitamin E succinate (the weight ratio of the three is 1:0.8:0.2);
14.5 parts of diethylene glycol monoethyl ether;
0.3 parts of polyethylene glycol.
The compound soft capsule is prepared according to the following steps:
(1) Preparing a liquid medicine: adding prescribed amount of butylphthalide, edaravone and Borneolum Syntheticum into mixture of prescribed amount of oil phase, emulsifier, auxiliary emulsifier and stabilizer, heating (35-40deg.C), stirring to dissolve the medicine uniformly, and cooling to room temperature to obtain medicinal liquid (lipid emulsion);
(2) Preparing a capsule liquid: about 150g of gelatin was taken and water was added to the mixture to expand the mixture. Heating 50g of glycerol, 300mg of methylparaben and 150g of water to 60-80 ℃ in a sol pot, uniformly mixing, adding gelatin liquid, stirring, and standing to obtain capsule liquid;
(3) Pressing soft capsules: the prepared medicinal oil liquid and capsule liquid are filled into an automatic rotary capsule rolling machine, and soft capsules are pressed at the ventilation position in a drying chamber with the temperature of 35-55 ℃.
Example 4
Prescription of soft capsule liquid medicine:
20 parts of butylphthalide;
4 parts of edaravone;
3 parts of borneol;
20 parts of propylene glycol monocaprate;
37.5 parts of a mixture of propylene glycol monocaprate and polyoxyethylene ether hydrogenated castor oil (the weight ratio of the propylene glycol monocaprate to the polyoxyethylene ether hydrogenated castor oil is 1:1);
14.5 parts of diethylene glycol monoethyl ether;
sodium sulfite 0.75 parts;
l-cysteine hydrochloride 0.25 parts.
The compound soft capsule is prepared according to the following steps:
(1) Preparing a liquid medicine: adding prescribed amount of butylphthalide, edaravone and Borneolum Syntheticum into mixture of prescribed amount of oil phase, emulsifier, auxiliary emulsifier and stabilizer, heating (35-40deg.C), stirring to dissolve the medicine uniformly, and cooling to room temperature to obtain medicinal liquid (lipid emulsion);
(2) Preparing a capsule liquid: about 150g of gelatin was taken and water was added to the mixture to expand the mixture. Heating 50g of glycerol, 300mg of methylparaben and 150g of water to 60-80 ℃ in a sol pot, uniformly mixing, adding gelatin liquid, stirring, and standing to obtain capsule liquid;
(3) Pressing soft capsules: the prepared medicinal oil liquid and capsule liquid are filled into an automatic rotary capsule rolling machine, and soft capsules are pressed at the ventilation position in a drying chamber with the temperature of 35-55 ℃.
Example 5
Unlike example 4, the recipe was 0.5 part of sodium sulfite, 0.5 part of L-cysteine hydrochloride, and the remainder were the same.
Prescription of soft capsule liquid medicine:
20 parts of butylphthalide;
4 parts of edaravone;
3 parts of borneol;
20 parts of propylene glycol monocaprate;
37.5 parts of a mixture of propylene glycol monocaprate and polyoxyethylene ether hydrogenated castor oil (the weight ratio of the propylene glycol monocaprate to the polyoxyethylene ether hydrogenated castor oil is 1:1);
14.5 parts of diethylene glycol monoethyl ether;
0.5 parts of sodium sulfite;
l-cysteine hydrochloride 0.5 parts.
The compound soft capsule is prepared according to the following steps:
(1) Preparing a liquid medicine: adding prescribed amount of butylphthalide, edaravone and Borneolum Syntheticum into mixture of prescribed amount of oil phase, emulsifier, auxiliary emulsifier and stabilizer, heating (35-40deg.C), stirring to dissolve the medicine uniformly, and cooling to room temperature to obtain medicinal liquid (lipid emulsion);
(2) Preparing a capsule liquid: about 150g of gelatin was taken and water was added to the mixture to expand the mixture. Heating 50g of glycerol, 300mg of methylparaben and 150g of water to 60-80 ℃ in a sol pot, uniformly mixing, adding gelatin liquid, stirring, and standing to obtain capsule liquid;
(3) Pressing soft capsules: the prepared medicinal oil liquid and capsule liquid are filled into an automatic rotary capsule rolling machine, and soft capsules are pressed at the ventilation position in a drying chamber with the temperature of 35-55 ℃.
Comparative example 1
Unlike example 4, the recipe contained no borneol and the remainder were the same.
Prescription of soft capsule liquid medicine:
20 parts of butylphthalide;
4 parts of edaravone;
20 parts of propylene glycol monocaprate;
37.5 parts of a mixture of propylene glycol monocaprate and polyoxyethylene ether hydrogenated castor oil (the weight ratio of the propylene glycol monocaprate to the polyoxyethylene ether hydrogenated castor oil is 1:1);
14.5 parts of diethylene glycol monoethyl ether;
sodium sulfite 0.75 parts;
l-cysteine hydrochloride 0.25 parts.
The compound soft capsule is prepared according to the following steps:
(1) Preparing a liquid medicine: adding prescribed amount of butylphthalide, edaravone and Borneolum Syntheticum into mixture of prescribed amount of oil phase, emulsifier, auxiliary emulsifier and stabilizer, heating (35-40deg.C), stirring to dissolve the medicine uniformly, and cooling to room temperature to obtain medicinal liquid (lipid emulsion);
(2) Preparing a capsule liquid: about 150g of gelatin was taken and water was added to the mixture to expand the mixture. Heating 50g of glycerol, 300mg of methylparaben and 150g of water to 60-80 ℃ in a sol pot, uniformly mixing, adding gelatin liquid, stirring, and standing to obtain capsule liquid;
(3) Pressing soft capsules: the prepared medicinal oil liquid and capsule liquid are filled into an automatic rotary capsule rolling machine, and soft capsules are pressed at the ventilation position in a drying chamber with the temperature of 35-55 ℃.
Comparative example 2
Unlike example 4, the recipe was 12 parts of borneol and the remainder were the same.
Prescription of soft capsule liquid medicine:
20 parts of butylphthalide;
4 parts of edaravone;
12 parts of borneol;
20 parts of propylene glycol monocaprate;
37.5 parts of a mixture of propylene glycol monocaprate and polyoxyethylene ether hydrogenated castor oil (the weight ratio of the propylene glycol monocaprate to the polyoxyethylene ether hydrogenated castor oil is 1:1);
14.5 parts of diethylene glycol monoethyl ether;
sodium sulfite 0.75 parts;
l-cysteine hydrochloride 0.25 parts.
The compound soft capsule is prepared according to the following steps:
(1) Preparing a liquid medicine: adding prescribed amount of butylphthalide, edaravone and Borneolum Syntheticum into mixture of prescribed amount of oil phase, emulsifier, auxiliary emulsifier and stabilizer, heating (35-40deg.C), stirring to dissolve the medicine uniformly, and cooling to room temperature to obtain medicinal liquid (lipid emulsion);
(2) Preparing a capsule liquid: about 150g of gelatin was taken and water was added to the mixture to expand the mixture. Heating 50g of glycerol, 300mg of methylparaben and 150g of water to 60-80 ℃ in a sol pot, uniformly mixing, adding gelatin liquid, stirring, and standing to obtain capsule liquid;
(3) Pressing soft capsules: the prepared medicinal oil liquid and capsule liquid are filled into an automatic rotary capsule rolling machine, and soft capsules are pressed at the ventilation position in a drying chamber with the temperature of 35-55 ℃.
Comparative example 3 (blank matrix soft capsule)
Unlike example 4, a blank matrix group was prepared without butylphthalide, edaravone and borneol in the recipe, the remainder being the same.
Prescription of soft capsule liquid medicine:
29.7 parts of propylene glycol monocaprylate;
49.5 parts of a mixture of propylene glycol monocaprate and polyoxyethylene ether hydrogenated castor oil (the weight ratio of the propylene glycol monocaprate to the polyoxyethylene ether hydrogenated castor oil is 1:1);
19.8 parts of diethylene glycol monoethyl ether;
sodium sulfite 0.75 parts;
l-cysteine hydrochloride 0.25 parts.
The compound soft capsule is prepared according to the following steps:
(1) Preparing a liquid medicine: mixing oil phase, emulsifier, auxiliary emulsifier and stabilizer uniformly, heating (35-40deg.C), stirring to dissolve the medicine uniformly, and standing at room temperature to obtain a mixture Bai Jizhi;
(2) Preparing a capsule liquid: about 150g of gelatin was taken and water was added to the mixture to expand the mixture. Heating 50g of glycerol, 300mg of methylparaben and 150g of water to 60-80 ℃ in a sol pot, uniformly mixing, adding gelatin liquid, stirring, and standing to obtain capsule liquid;
(3) Pressing soft capsules: the prepared medicinal oil liquid and capsule liquid are filled into an automatic rotary capsule rolling machine, and soft capsules are pressed at the ventilation position in a drying chamber with the temperature of 35-55 ℃.
Comparative example 4 (Soft Capsule containing Butylphthalide)
Unlike example 4, edaravone and borneol are not added to the formulation, and the remainder are the same.
Prescription of soft capsule liquid medicine:
20 parts of butylphthalide;
23.7 parts of propylene glycol monocaprate;
39.5 parts of a mixture of propylene glycol monocaprate and polyoxyethylene ether hydrogenated castor oil (the weight ratio of the propylene glycol monocaprate to the polyoxyethylene ether hydrogenated castor oil is 1:1);
15.8 parts of diethylene glycol monoethyl ether;
sodium sulfite 0.75 parts;
l-cysteine hydrochloride 0.25 parts.
The compound soft capsule is prepared according to the following steps:
(1) Preparing a liquid medicine: adding butylphthalide into the mixture of oil phase, emulsifier, auxiliary emulsifier and stabilizer, heating (35-40deg.C), stirring to dissolve the medicine uniformly, and cooling to room temperature to obtain medicinal liquid (lipid emulsion);
(2) Preparing a capsule liquid: about 150g of gelatin was taken and water was added to the mixture to expand the mixture. Heating 50g of glycerol, 300mg of methylparaben and 150g of water to 60-80 ℃ in a sol pot, uniformly mixing, adding gelatin liquid, stirring, and standing to obtain capsule liquid;
(3) Pressing soft capsules: the prepared medicinal oil liquid and capsule liquid are filled into an automatic rotary capsule rolling machine, and soft capsules are pressed at the ventilation position in a drying chamber with the temperature of 35-55 ℃.
Comparative example 5 (edaravone-containing Soft Capsule)
Unlike example 4, butylphthalide and borneol are not added to the formulation, and the remainder are the same.
Prescription of soft capsule liquid medicine:
4 parts of edaravone;
28.5 parts of propylene glycol monocaprylate;
47.5 parts of a mixture of propylene glycol monocaprate and polyoxyethylene ether hydrogenated castor oil (the weight ratio of the propylene glycol monocaprate to the polyoxyethylene ether hydrogenated castor oil is 1:1);
19 parts of diethylene glycol monoethyl ether;
sodium sulfite 0.75 parts;
l-cysteine hydrochloride 0.25 parts.
The compound soft capsule is prepared according to the following steps:
(1) Preparing a liquid medicine: adding the edaravone with the prescription amount into the mixture of the oil phase, the emulsifier, the auxiliary emulsifier and the stabilizer with the prescription amount, heating (35-40 ℃) and stirring to dissolve the medicine uniformly, and cooling to room temperature to obtain liquid medicine (lipid emulsion);
(2) Preparing a capsule liquid: about 150g of gelatin was taken and water was added to the mixture to expand the mixture. Heating 50g of glycerol, 300mg of methylparaben and 150g of water to 60-80 ℃ in a sol pot, uniformly mixing, adding gelatin liquid, stirring, and standing to obtain capsule liquid;
(3) Pressing soft capsules: the prepared medicinal oil liquid and capsule liquid are filled into an automatic rotary capsule rolling machine, and soft capsules are pressed at the ventilation position in a drying chamber with the temperature of 35-55 ℃.
Comparative example 6 (Soft Capsule containing borneol)
Unlike example 4, butylphthalide and edaravone were not added to the formulation, the remainder being the same.
Prescription of soft capsule liquid medicine:
3 parts of borneol;
28.8 parts of propylene glycol monocaprylate;
48 parts of a mixture of propylene glycol monocaprate and polyoxyethylene ether hydrogenated castor oil (the weight ratio of the propylene glycol monocaprate to the polyoxyethylene ether hydrogenated castor oil is 1:1);
19.2 parts of diethylene glycol monoethyl ether;
sodium sulfite 0.75 parts;
l-cysteine hydrochloride 0.25 parts.
The compound soft capsule is prepared according to the following steps:
(1) Preparing a liquid medicine: adding Borneolum Syntheticum with prescription amount into the mixture of oil phase, emulsifier, auxiliary emulsifier and stabilizer, heating (35-40deg.C), stirring to dissolve the medicine uniformly, and cooling to room temperature to obtain medicinal liquid (lipid emulsion);
(2) Preparing a capsule liquid: about 150g of gelatin was taken and water was added to the mixture to expand the mixture. Heating 50g of glycerol, 300mg of methylparaben and 150g of water to 60-80 ℃ in a sol pot, uniformly mixing, adding gelatin liquid, stirring, and standing to obtain capsule liquid;
(3) Pressing soft capsules: the prepared medicinal oil liquid and capsule liquid are filled into an automatic rotary capsule rolling machine, and soft capsules are pressed at the ventilation position in a drying chamber with the temperature of 35-55 ℃.
Comparative example 7 (Soft Capsule containing edaravone and borneol)
Unlike example 4, butylphthalide was not added to the formulation, and the remainder were the same.
Prescription of soft capsule liquid medicine:
4 parts of edaravone;
3 parts of borneol;
27.6 parts of propylene glycol monocaprate;
46 parts of a mixture of propylene glycol monocaprate and polyoxyethylene ether hydrogenated castor oil (the weight ratio of the propylene glycol monocaprate to the polyoxyethylene ether hydrogenated castor oil is 1:1);
18.4 parts of diethylene glycol monoethyl ether;
sodium sulfite 0.75 parts;
l-cysteine hydrochloride 0.25 parts.
The compound soft capsule is prepared according to the following steps:
(1) Preparing a liquid medicine: adding the edaravone and borneol with the prescription amount into the mixture of the oil phase, the emulsifier, the auxiliary emulsifier and the stabilizer with the prescription amount, heating (35-40 ℃) and stirring to dissolve the medicine uniformly, and cooling to room temperature to obtain liquid medicine (lipid emulsion);
(2) Preparing a capsule liquid: about 150g of gelatin was taken and water was added to the mixture to expand the mixture. Heating 50g of glycerol, 300mg of methylparaben and 150g of water to 60-80 ℃ in a sol pot, uniformly mixing, adding gelatin liquid, stirring, and standing to obtain capsule liquid;
(3) Pressing soft capsules: the prepared medicinal oil liquid and capsule liquid are filled into an automatic rotary capsule rolling machine, and soft capsules are pressed at the ventilation position in a drying chamber with the temperature of 35-55 ℃.
3. Measurement of lipid milk particle size
The measuring method comprises the following steps: the prepared lipid emulsion is dissolved and diluted by 10 times by distilled water, and the particle size distribution of the composite particles is respectively measured by a laser particle sizer. The results are shown in the following table:
Table 1.
Wherein PDI (Polymer dispersity index) refers to a polymer dispersibility index for describing the molecular weight distribution of a polymer, the greater the PDI, the broader the molecular weight distribution; the smaller the PDI, the more uniform the molecular weight distribution.
The value of the Zeta potential is related to the stability of the colloidal dispersion and is a measure of the strength of the mutual repulsion or attraction between particles. The smaller the molecule or dispersed particle, the higher the absolute value of the Zeta potential (positive or negative), the more stable the system, i.e. the dissolution or dispersion can resist aggregation. Conversely, the lower the Zeta potential (positive or negative), the more prone it is to coagulation or agglomeration, i.e. the attractive force exceeds the repulsive force, and the dispersion is broken down to coagulate or agglomerate (note that the Zeta potential absolute value represents its stability and positive and negative represent what charge the particles have).
As can be seen from the above table, the lipid emulsion-type capsule liquid prepared in examples 1 to 5 has a uniform particle size distribution and is stable in dispersion.
4. Determination of butylphthalide content in compound soft capsule
The measuring method comprises the following steps: high performance liquid chromatography.
Octadecylsilane chemically bonded silica is used as a filler for chromatographic conditions and system applicability tests; methanol-water (65:35) was used as mobile phase, and the detection wavelength was 227nm. And 20 mu L of the system applicability test solution under the relevant material item is taken and injected into a liquid chromatograph, and the separation degree of the butylphthalide peak and the impurity peak is more than 1.0.
The determination method precisely weighs a proper amount (about 50mg equivalent to butylphthalide) of the compound soft capsule, puts the compound soft capsule into a 50ml measuring flask, adds chloroform to dissolve and dilute to scale, shakes evenly, filters, precisely measures 5ml of subsequent filtrate, puts the filtrate into a 50ml measuring flask, adds methanol to dilute to scale, shakes evenly, takes 20 mu L of solution as a test sample solution, and fills the solution into a liquid chromatograph, and records a chromatogram.
And (3) taking 50mg of butylphthalide reference substance, placing in a 50mL measuring flask, adding methanol to dissolve to a scale, shaking uniformly, precisely measuring 5mL of butylphthalide reference substance in the 50mL measuring flask, adding methanol to dilute to the scale, shaking uniformly, and measuring by the same method. The content (mass fraction,%) of butylphthalide in the prepared compound soft capsule is calculated by the peak area according to an external standard method. The results were as follows:
table 2.
It can be seen that the content of the butylbenzene peptide in the compound capsule preparation prepared in examples 1-5 is relatively similar to that in the prescription.
5. Determination of edaravone content in compound soft capsule
The measuring method comprises the following steps: high performance liquid chromatography.
Chromatographic conditions and system suitability test: octadecylsilane chemically bonded silica is used as a filler; the detection wavelength was 245nm with 0.05mol/L ammonium dihydrogen phosphate solution (pH adjusted to 3.5 with 20% phosphoric acid solution) -methanol (50:50) as mobile phase.
Assay: and precisely weighing a proper amount of the compound soft capsule, diluting with a mobile phase to prepare a solution containing about 50 mug of edaravone in each 1mL, taking the solution as a test solution, precisely weighing 20 mug of the test solution, injecting the test solution into a liquid chromatograph, and recording a chromatogram. And (3) taking a proper amount of edaravone reference substance, precisely weighing, adding a mobile phase for dissolution, and quantitatively diluting to prepare a solution containing about 50 mug per 1mL, and determining by the same method. And calculating the content of edaravone in the prepared compound soft capsule according to an external standard method and peak area.
Table 3.
| Measuring the edaravone content, percent | Edaravone content in the prescription,% | |
| Example 1 | 3.41 | 3.5 |
| Example 2 | 0.93 | 1 |
| Example 3 | 3.72 | 3.7 |
| Example 4 | 4.30 | 4 |
| Example 5 | 4.16 | 4 |
It can be seen that the edaravone content and the edaravone content in the prescription are relatively close in the compound capsule preparation prepared in examples 1 to 5.
6. In vitro pharmacodynamic experiments
6.1 in vitro cell experiment Material
6.1.1 pharmaceutical products
Test drug: the compound soft capsules of examples 1-5 and comparative examples 1-2.
6.1.2 cell culture
Human brain microvascular endothelial cell strain HBMEC is cultured in DMEM medium containing 10% fetal bovine serum, and subjected to stationary culture at 37 ℃ under the condition of 5% CO2, and cells in logarithmic growth phase are taken for experiment.
6.2 establishment and evaluation of in vitro blood brain Barrier model
6.2.1 establishment of in vitro blood brain Barrier model
Taking HBMEC cells in logarithmic growth phase at 2×10 5 Cell density per mL of 500. Mu.L of cells per well was inoculated into a 12-well Transwell chamber (0.4. Mu.m, corning Co.) and 1.5mL of 10% FBS-containing DMEM medium was used as a receiving well at 37℃and 5% CO 2 And (3) standing and culturing, namely changing the liquid every 2 days, culturing until tight connection is formed between cells, and then carrying out a transport experiment.
6.2.2 evaluation of in vitro blood brain Barrier model by transendothelial resistance method
The transmembrane resistance (The Transepithelial Electrical Resistance, TEER) was measured by a cell resistance meter. TEER was measured from day 3 of the Transwell chamber by cell inoculation, and the old culture broth was drained and used without Ca 2+ And Mg (magnesium) 2+ The Hank's buffer solution of (C) was washed 2 times, and the cell line resistance value of the inoculated cell line, and the cell line resistance value of the non-inoculated cell line, were measured, respectively, and the measurement was completed and replaced with a new culture solution.
Ω endo thelial ＝Ω total -Ω insert
TEER value is the product of resistance value Ω and effective area S of Transwell cell filter, and the effective area of 12-well plate cell is 1.12cm2.
TEER＝Ω endo thelial ×S
6.3 evaluation of transport efficiency of Butylphthalide, edaravone and borneol compound soft capsules
The in vitro BBB model is cultivated to form tight connection on the 11 th day, and the transportation efficiency of the compound soft capsule can be examined. Serum-free DMEM medium containing 0.5mg/mL of the above drugs was added to each donor pool of the different groups, and 1.5mL of serum-free DMEM medium was added to the recipient pool. Placing in a shaker, taking 300 μl of sample solution at 37deg.C and shaking speed of 80rpm at 30, 60, 90, 120, 150, 180min, and supplementing 300 μl of fresh culture solution. Each set was provided with 3 auxiliary wells. 300 mu L of acetonitrile is added into the sample solution, vortex is carried out for 30 seconds, ultrasonic is carried out for 15 minutes, centrifugation is carried out for 10 minutes at 12000rpm, the concentration of butylphthalide and edaravone is measured according to the HPLC method under the conditions of example 5 and example 6, and the transport efficiency at different times is calculated.
6.4 transendothelial resistance measurement results
Human Brain Microvascular Endothelial Cells (HBMEC) are used for constructing an in-vitro blood brain barrier model, TEER is used as an investigation index in the model establishment process, and when the TEER reaches 200Ω & cm 2 In this case, a substance transport study can be performed. As shown in FIG. 7, the TEER value of the drug of example 4 had reached (213.41.+ -. 14.61) Ω·cm at 11 days 2 。
6.5 Trans in vitro model Transporter efficiency measurement results
As shown in FIGS. 8 and 9, the transport efficiency increases with the increase of the culture time. In fig. 8 and 9, the reference drug is the drug prepared in comparative example 1, and the test drug is the drug prepared in example 4, and it can be seen that after incubation for 180min, the cumulative transport efficiencies of butylphthalide and edaravone in the comparative example 1 reference drug group without borneol are 7.45% and 6.32%, respectively; and the accumulated transfer efficiency of the butylphthalide and the edaravone in the test drug group of the embodiment 4 containing the borneol is respectively 12.54 percent and 10.67 percent, which proves that the borneol can promote the butylphthalide and the edaravone in the soft capsule to permeate the blood brain barrier.
The cumulative transport efficiency of butylphthalide and edaravone after 180min incubation of examples 1-3, comparative example 2 was tested in the same manner. The results are shown in the following table:
Table 4.
It can be seen that the compound capsule preparation prepared in the embodiments 1-5 of the invention has obviously improved butylphthalide accumulation and transport efficiency and edaravone accumulation and transport efficiency after 180 min. Compared with the compound preparation containing borneol in comparative example 1, the compound preparation containing borneol has the advantages that the accumulated transport efficiency of butylphthalide and the accumulated transport efficiency of edaravone are improved to different degrees, and the borneol can be proved to have a synergistic effect with butylphthalide and edaravone, so that the transport of butylphthalide and edaravone is promoted. Meanwhile, as can be seen from comparative example 2, after the amount of borneol is increased, the transfer efficiency is reduced, which indicates that the synergistic effect of the three should be controlled within a reasonable ratio range. Example 4 is a preferred example, in which the mass ratio of butylphthalide, edaravone and borneol is 20:4: and 3, obtaining the optimal synergistic effect. Meanwhile, the mass ratio of the butylphthalide and the edaravone also affects the synergistic effect of the butylphthalide and the edaravone, so that the transport efficiency is reduced simultaneously, for example, in the embodiment 2, the cumulative transport efficiency of the butylphthalide is only 8.26%, and the cumulative transport efficiency of the edaravone is 7.94%, and is obviously lower than that of other embodiments although the mass ratio of the edaravone is improved compared with that of a non-ice-flake group.
6.6SK-N cell Hydrogen peroxide injury model fumbling experiments
SK-N-SH cells were cultured in 96-well plates, 2X 10 4 160 μl of cell suspension per well was incubated overnight. The following day was given a high, medium, and low dose of 20. Mu.l of the drug to be tested (example 4, comparative examples 3-6) at 10. Mu.l of hydrogen peroxide (model group) at a final concentration of 300. Mu.M at 11. Mu.l of 30. Cell viability was measured at 15 o' clock 30 plus CCK-8. (data for each well in the following table = OD value detected per well-OD value for blank group
The results are shown in the following table:
table 5.
## P<0.01 The 300 μm model group was compared with the control group, * P<compared to the model group of 0.05 and 300 μm, ** P<0.01 was compared to the 300 μm model set.
7. In vivo pharmacodynamic experiments
7.1 pharmaceutical products
Test drug: the compound soft capsules of example 4, comparative example 3 and comparative example 7.
7.2 animal model
The animals model 30 (15 males and 15 females) for the progressive freezing disease were dosed by gavage (2 times daily) at a dose of 5mg/kg daily, starting from model build to 113 days, and the behavioural scores were recorded.
7.3 comparison of behavioral changes in groups of animals with model of progressive freezing syndrome after administration
Behavioural scoring criteria: the 1-5 score method studied by Vercelli et al, 1-5 score, is defined as follows:
5: healthy without any paralysis symptoms; 4: mild gait instability and hind limb paralysis symptoms; 3: obvious paralysis and unstable gait; 2: complete paralysis of hind limbs, and animals only crawl by forelimbs; 1: hind limb complete paralysis, the animal mainly takes a lateral position, and/or can not turn over or lose more than 20% of the initial weight after turning over. Animal death was scored as 0 points. Fig. 10 is a graph of experimental results. It can be seen that the medicine of the embodiment of the invention has good treatment and inhibition effects on the progressive freezing syndrome.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (19)
1. A pharmaceutical composition, characterized by comprising the following components in mass ratio of 5-30:0.5-10:0.1-10 parts of butylphthalide, edaravone and borneol.
2. The pharmaceutical composition according to claim 1, wherein the butylphthalide is a racemate, a levorotatory or a dextrorotatory body.
3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a mass ratio of 10-25:1-6:1-5 parts of butylphthalide, edaravone and borneol.
4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a mass ratio of 15-25:3-6:2-5 parts of butylphthalide, edaravone and borneol.
5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a mass ratio of 20:4:3, butylphthalide, edaravone and borneol.
6. A soft capsule liquid comprising the pharmaceutical composition of any one of claims 1-5 and one or more pharmaceutically acceptable additives and/or excipients.
7. The soft capsule medical fluid of claim 6, wherein the pharmaceutically acceptable carrier and/or excipient is an oil phase, an emulsifier, a co-emulsifier, and a stabilizer.
8. The soft capsule liquid medicine according to claim 7, wherein the soft capsule liquid medicine comprises 5-30 parts of butylphthalide, 0.5-10 parts of edaravone, 0.1-10 parts of borneol, 20-50 parts of oil phase, 20-50 parts of emulsifier, 5-25 parts of co-emulsifier and 0.01-5 parts of stabilizer.
9. The soft capsule liquid medicine according to claim 8, wherein the soft capsule liquid medicine comprises 15-25 parts of butylphthalide, 3-6 parts of edaravone, 2-5 parts of borneol, 20-25 parts of oil phase, 35-45 parts of emulsifier, 15-20 parts of co-emulsifier and 0.1-2 parts of stabilizer.
10. The soft capsule medical fluid of any one of claims 7-9, wherein the oil phase is at least one of propylene glycol monocaprylate, corn oil.
11. The soft capsule medical fluid of claim 10, wherein the oil phase is propylene glycol monocaprate.
12. The soft capsule medical fluid of any one of claims 7-9, wherein the emulsifier is at least one of propylene glycol monocaprate, polyoxyethylene ether hydrogenated castor oil, polyethylene glycol 1000 vitamin E succinate.
13. The soft capsule medical fluid of claim 12, wherein the emulsifier is propylene glycol monocaprate and polyoxyethylene ether hydrogenated castor oil in a weight ratio of 1: 1.
14. The soft capsule medical fluid of any one of claims 7-9, wherein the co-emulsifier is diethylene glycol monoethyl ether.
15. The soft capsule medical solution according to any one of claims 7 to 9, wherein the stabilizer is at least one of sodium sulfite, L-cysteine hydrochloride and polyethylene glycol.
16. The soft capsule medical fluid of claim 15, wherein the stabilizer is a mixture of 3:1 sodium sulfite and L-cysteine hydrochloride.
17. A compound soft capsule, which is characterized by comprising the soft capsule liquid medicine and capsule wall material according to any one of claims 6-16.
18. The compound soft capsule of claim 17, wherein the capsule wall material comprises pharmaceutically acceptable gelatin, acacia, glycerin, sorbitol, iron trioxide, titanium dioxide, methyl paraben, ethyl paraben, sorbitol, and purified water.
19. The method for preparing the compound soft capsule of claim 17 or 18, which is characterized by comprising the following steps:
(1) Preparing a liquid medicine: adding butylphthalide, edaravone and borneol into the mixture of oil phase, emulsifier, auxiliary emulsifier and stabilizer, heating and stirring to dissolve the medicine uniformly, and cooling to room temperature to obtain liquid medicine;
(2) Preparing a capsule liquid: adding capsule wall material formula components into purified water to obtain capsule liquid;
(3) Pressing soft capsules: and (3) filling the prepared medicinal oil liquid and capsule liquid into an automatic rotary capsule rolling machine, and pressing to obtain the soft capsules.
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