CN110693882A - Sublingual pharmaceutical composition - Google Patents
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- CN110693882A CN110693882A CN201810748134.XA CN201810748134A CN110693882A CN 110693882 A CN110693882 A CN 110693882A CN 201810748134 A CN201810748134 A CN 201810748134A CN 110693882 A CN110693882 A CN 110693882A
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- edaravone
- pharmaceutical composition
- borneol
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- excipient
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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Abstract
The invention discloses a sublingual administration preparation and a preparation method thereof, wherein the active ingredients of the sublingual administration preparation are edaravone and (+) 2-borneol, and the inactive ingredients comprise excipient, filler, adhesive, disintegrant, lubricant, glidant, coating material and the like. The sublingual administration preparation can avoid liver first pass effect, and has the advantages of good sample stability, convenient transportation, convenient use and the like.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a sublingual pharmaceutical composition and a preparation method thereof.
Background
Edaravone (chemical name: 3-methyl-1-phenyl-2-pyrazolin-5-one) is marketed cerebral nerve protective agent: (Yakugaku Zasshi. 2004, 124(3): 99-111). Research shows that edaravone has antioxidant activity, can obviously improve the nerve defect symptoms of cerebral ischemia reperfusion animals, reduce the infarct size, reduce the degree of brain injury, relieve cerebral edema and inhibit lipid peroxidation of damaged brain tissues.
Edaravone
(formula C)10H10N2O, molecular weight 174.20)
(+) -2-borneol is the main ingredient of a common traditional Chinese medicine, namely natural borneol, and the borneol has the effects of resuscitation by resuscitation, curtain by fragrance and ascending by guiding drugs, and is often used as a guiding drug to improve the treatment effect of other drugs; ben Cao Yan Yi (the Yan Yi of materia Medica) points out that borneol is weak in one way and active in adjuvant therapy. Animal experiments and in vitro experiments show that: borneol has the function of promoting the medicine to penetrate blood brain barrier.
Camphol alcohol
(formula C)10H18O; molecular weight 154.25)
The invention patent (CN 101848711A) entitled "a pharmaceutical composition and application thereof in preparing medicaments for treating cerebrovascular diseases" discloses application of a composition of edaravone and (+) -2-borneol injection in a specific proportion in preparing medicaments for treating cerebrovascular diseases, in particular to medicaments for treating ischemic cerebrovascular diseases.
Some acute diseases need to be relieved quickly, generally, intramuscular injection or intravenous administration is the first choice method for emergency treatment, but intramuscular injection or intravenous injection can cause pain and stimulation at the injection site, operation of medical staff is needed, and injection products and the like are needed, so that the application is limited by certain medical treatment, and the method is not suitable for patients suffering from diseases outside hospitals. The sublingual preparation is directly absorbed by sublingual mucosa, the sublingual mucosa has large surface area and strong permeability, a large number of capillaries below the mucosa are gathered to internal jugular veins and directly enter blood circulation through superior vena cava, the medicine is quickly absorbed after administration, the onset is quick, the quantification is accurate, the use is convenient, and the first pass effect of oral medicine is avoided. Compared with injections, the sublingual tablet greatly improves the convenience of medication and the compliance of clinical patients.
Disclosure of Invention
The invention aims to provide a sublingual pharmaceutical composition which comprises edaravone or a salt thereof and (+) -2-borneol. The sublingual tablet has to be released quickly to reach a certain blood concentration so as to exert the treatment effect. The invention provides a sublingual pharmaceutical composition, and main medicaments can be quickly released and absorbed under the tongue.
In order to achieve the purpose, the invention adopts the following technical scheme:
the sublingual tablet containing the composition of edaravone and (+) -2-borneol is characterized by containing active ingredients of edaravone or a salt thereof and (+) -2-borneol and pharmaceutically acceptable auxiliary materials, wherein the pharmaceutically acceptable auxiliary materials comprise an excipient, the excipient is one or more selected from mannitol, lactose, dextran, cysteine, glycine and cyclodextrin, and the preferred excipient is mannitol.
In the sublingual composition, the weight ratio of edaravone to (+) -2-borneol in terms of free base is 4:1 to 1:1, preferably, the weight ratio of edaravone to (+) -2-borneol in terms of free base is 2:1 to 1:1, and more preferably, the weight ratio of edaravone to (+) -2-borneol in terms of free base is 4: 1.
In the sublingual composition, the filler is selected from lactose, starch, sucrose, mannitol, sorbitol, microcrystalline cellulose, calcium dihydrogen phosphate, etc.
In the sublingual administration composition, the adhesive is selected from sodium carboxymethylcellulose, hypromellose, hydroxypropyl cellulose, povidone, starch, ethyl cellulose, methyl cellulose and the like.
In the sublingual administration composition, the disintegrating agent is selected from sodium carboxymethyl starch, hydroxypropyl cellulose, croscarmellose sodium, crospovidone, starch and the like.
The preparation method of the sublingual administration composition comprises the following steps: mixing edaravone with (+) -2-camphanol, excipient, filler, binder, disintegrant, lubricant and glidant, and tabletting.
The preparation method of the sublingual administration composition comprises the following steps: mixing the edaravone with (+) -2-borneol, an excipient, a filler and an adhesive, granulating, adding a disintegrant, a lubricant and a glidant, uniformly mixing, and tabletting.
The sublingual composition can be used for treating cerebrovascular diseases.
Drawings
Figure 1 examples 1 to 5 dissolution profiles.
Detailed Description
The invention discloses a sublingual administration preparation of edaravone and (+) -2-borneol, which can be realized by a person skilled in the art by properly improving process parameters or prescription ratio by taking the contents of the invention as reference and combining the principle of pharmacy. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention. While the invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the art that the techniques of the invention can be implemented and practiced with modification, or with appropriate modification, and combinations of the methods and applications described herein without departing from the spirit, scope, and spirit of the invention.
Edaravone mentioned in the examples is 3-methyl-1-phenyl-2-pyrazolin-5-one.
The present invention is further illustrated by the following examples, which are not intended to limit the invention in any way.
Example 1
The preparation method comprises the following steps: mixing (+) -2-borneol, edaravone, mannitol, hydroxypropyl methylcellulose, croscarmellose sodium and magnesium stearate uniformly, and tabletting.
Example 2
The preparation method comprises the following steps: mixing (+) -2-borneol, edaravone, lactose, hydroxypropyl methylcellulose, croscarmellose sodium and magnesium stearate uniformly, and tabletting.
Example 3
The preparation method comprises the following steps: mixing (+) -2-borneol, edaravone, microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose sodium and magnesium stearate uniformly, and tabletting.
Example 4
The preparation method comprises the following steps: mixing (+) -2-borneol, edaravone, betacyclodextrin, microcrystalline cellulose, hydroxypropyl methylcellulose, croscarmellose sodium and magnesium stearate uniformly, and tabletting.
Example 5
The preparation method comprises the following steps: mixing (+) -2-borneol, edaravone, betacyclodextrin, microcrystalline cellulose and hydroxypropyl methylcellulose, granulating, adding hydroxypropyl methylcellulose, croscarmellose sodium and magnesium stearate, mixing, and tabletting.
Example 6
The stability test results are as follows: a proper amount of samples in the examples 1-5 are taken, the samples are packaged on the market in a simulated mode, the samples are placed for 10 days and 30 days at the temperature of 40 ℃ and 60 ℃, the properties, the contents and related substances of the samples are measured, and the results are shown in the following table:
example 7
Dissolution rate determination test method: taking a sample, taking 900 ml of water as a dissolution medium (wherein 250 ml of water is adopted as the dissolution medium in examples 3 and 4) according to a dissolution and release determination method of Chinese pharmacopoeia 2015 edition (fourth 0931, second method), rotating at 50rpm, operating according to the method, respectively sampling at different time points, filtering by a 0.8 mu m filter membrane, and taking a subsequent filtrate as a sample solution; taking a proper amount of edaravone control, adding 20 mmol/L ammonium acetate/acetonitrile (80: 20) to dissolve and dilute to about 0.02 mg/ml for later use. And (4) measuring the ultraviolet absorbance of the test solution under the condition of 254 nm, and calculating the dissolution rate of the sample.
Example 8
Sublingual tablet for protecting focal cerebral ischemia reperfusion injury
1 materials and methods
1.1 Experimental animals
Sprague-Dawley (SD) rats, male, clean grade, body weight 260-
1.2 test drugs
Sublingual tablets are prepared according to the prescription proportion of example 1, and the three specifications respectively contain 0.64 mg of edaravone and 0.16mg of camphanol (3 mg/kg dosage group medication); 1.92 mg of edaravone and 0.48 mg of camphol (9 mg/kg dose for group administration); edaravone 5.76 mg and borneol 1.44 mg (27 mg/kg dose group).
The compound edaravone injection has the specification: 5 mL of 12.5 mg, produced by Nanjing Xian Shen Dongyuan pharmaceutical Co.
Experimental methods
1.3.1 preparation of focal cerebral ischemia reperfusion model
A Middle Cerebral Artery Occlusion (MCAO) cerebral ischemia reperfusion model was prepared by an internal carotid artery embolization method. After animals were anesthetized with 7% chloral hydrate (6 ml/kg), fixed on an operating table in the prone position, the skin was sterilized, the neck was opened in the middle, the right common carotid artery, external carotid artery, and internal carotid artery were separated, the vagus nerve was gently peeled off, the external carotid artery was ligated and cut off, the internal carotid artery was followed forward, and the pterygopalatine artery was ligated. Clamping the proximal end of common carotid artery, making an incision from the distal end of the ligature of external carotid artery, inserting a nylon thread with the outer diameter of 0.285 mm, entering the internal carotid artery after the common carotid artery bifurcates, then slowly inserting until slight resistance exists (about 20 mm from the bifurcation), blocking all blood supply of the middle cerebral artery, slightly pulling out the nylon thread after 2.0 h of right cerebral ischemia, recovering the blood supply for reperfusion, suturing the skin, sterilizing
1.3.2 animal grouping and administration
The experimental animals are divided into 3 dosage groups (3 mg/kg, 9 mg/kg and 27 mg/kg) of the sublingual tablet of the composition, a positive drug compound edaravone group (3 mg/kg) and a model group, and the total is 5 groups. After preparation of the cerebral ischemia model, animals were assigned to each group with equal probability blindly. The animals in the composition group are instantly administered sublingually to sublingual tablets with corresponding specifications in reperfusion, 1 tablet is taken by each rat, the mouth of each rat is fixed, and the tablets are prevented from falling out or sliding into the gastrointestinal tract until the tablets are completely absorbed; the animals of the positive group were dosed 1 time in the tail vein immediately after reperfusion, and the animals of the model group were given an equal volume of physiological saline. Neurological deficit symptoms were assessed 24 hours after cerebral ischemia, and animals were sacrificed, brains were removed, stained, and photographed to determine cerebral infarct size.
Neurological deficit symptom scoring and cerebral infarction area determination
The symptom of neurological deficit was assessed using a modified Bederson 5-score. The nerve defect symptoms of rats after cerebral ischemia are evaluated by adopting a single blind method, namely animals are marked according to groups by a test designer, the testers scoring the nerve defect symptoms do not know the grouping condition of the animals, after the scoring is finished, the scorers present the scoring results of various marks to the designer, and the designer uncovers the blind to obtain the score of each animal of each test group.
Attached table: method for scoring Bederson 5 for symptoms of neurological deficit
0: when the tail is lifted and suspended, the two forelimbs of the animal extend to the direction of the floor without other behavior defects
1: when the tail is lifted and suspended, the operation of the animal shows that the elbow of the left forelimb is flexed, the shoulder is rotated inwards, the elbow is expanded outwards and is tightly attached to the chest wall
2: the animal is placed on a smooth plate, and resistance is reduced when the side shoulder of the pushing operation moves to the opposite side
3: when the animal walks freely, the animal circulates or rotates towards the opposite side of the operation
4: flaccid limbs and trunk without spontaneous movement
The method comprises the steps of measuring the degree of cerebral infarction, taking out the brain by cutting off the head after an animal is killed, removing olfactory bulbs, cerebellum and low brain stem, flushing blood stains on the surface of the brain with normal saline, sucking residual water stains on the surface, placing at-20 ℃ for 20 min, taking out, immediately making a coronal section vertically downwards on a sight line cross plane, cutting one piece backwards at intervals of 2 mm, placing the brain piece in 2% TTC dye solution for incubation (at 37 ℃ for 90min), dyeing normal brain tissues into deep red, enabling ischemic brain tissues to be pale, flushing with normal saline, quickly arranging the brain piece in a row from front to back in sequence, sucking residual water stains on the surface, and taking a picture.
And processing the picture by using image analysis software, calculating the corresponding volume of the left brain and the volume of the infarct focus according to a formula, and calculating the percentage of the infarct focus.
Infarct volume calculation method:
V=t (A1+ A2+ A3+ ………+An)
t is the slice thickness and A is the infarct size.
×(VC-VL)/VC
% I is the infarct volume percentage, VC is the control side (left hemisphere) brain volume, and VL is the infarct side (right hemisphere) non-infarct zone volume.
Results of the experiment
2.1 Effect on symptoms of neurological deficits
The degree of the neurological deficit symptoms of the animals in each group is shown in table 1, and compared with the model group, 3 sublingual doses (3, 9 and 27 mg/kg) and 3 positive compound edaravone (3 mg/kg) of the composition can obviously improve the neurological deficit symptoms (p =0.022, 0.004, 0.005 and 0.013).
TABLE 1 Effect of Edaravone and (+) -2-borneol compound sublingual administration on neurological deficit symptoms
X + -SD. P <0.05 compared to model group
2.2 Effect on cerebral infarct size
The influence on the cerebral infarction area is shown in table 2, compared with a model group, the sublingual 3 doses (3, 9 and 27 mg/kg) of the composition and the positive medicine compound edaravone can obviously reduce the cerebral infarction area after the animal is subjected to ischemia reperfusion (p =0.015, 0.011, 0.008 and 0.022).
Influence of compound sublingual administration of Epimedium 2 edaravone and (+) -2-camphanol on cerebral infarction area
X + -SD, p <0.05, p <0.01, compared to model group
Experimental data show that the sublingual tablet can achieve the drug effect equivalent to that of an injection.
Claims (10)
1. A sublingual tablet containing a composition of edaravone and (+) -2-borneol is characterized by containing active ingredients of edaravone or a salt thereof and (+) -2-borneol and pharmaceutically acceptable auxiliary materials, wherein the pharmaceutically acceptable auxiliary materials comprise an excipient, a filling agent, a bonding agent, a disintegrating agent, a lubricant, a glidant, a coating material and the like.
2. The pharmaceutical composition of claim 1, wherein the weight ratio of edaravone to (+) -2-borneol on a free base basis is from 4:1 to 1: 1.
3. The pharmaceutical composition of claim 1, wherein the weight ratio of edaravone to (+) -2-borneol on a free base basis is 4: 1.
4. The pharmaceutical composition of claim 1, wherein the excipient is one or more of mannitol, lactose, dextran, cysteine, glycine, and cyclodextrin.
5. The pharmaceutical composition of claim 1, wherein the filler is lactose, starch, sucrose, mannitol, sorbitol, microcrystalline cellulose, calcium dihydrogen phosphate, or the like.
6. The pharmaceutical composition of claim 1, wherein the binder is sodium carboxymethylcellulose, hypromellose, hydroxypropyl cellulose, povidone, starch, ethyl cellulose, methyl cellulose, or the like.
7. The pharmaceutical composition of claim 1, wherein the disintegrant is sodium carboxymethyl starch, hydroxypropyl cellulose, croscarmellose sodium, crospovidone, starch, or the like.
8. The process for the preparation of a pharmaceutical composition according to any one of claims 1 to 7, comprising the steps of: mixing edaravone with (+) -2-camphanol, excipient, filler, binder, disintegrant, lubricant and glidant, and tabletting.
9. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 7, comprising the steps of: mixing the edaravone with (+) -2-borneol, an excipient, a filler and an adhesive, granulating, adding a disintegrant, a lubricant and a glidant, uniformly mixing, and tabletting.
10. The sublingual tablet according to the present invention as claimed in claims 1 to 9, for use in the preparation of a medicament for the treatment of cerebrovascular diseases.
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| CN201810748134.XA CN110693882A (en) | 2018-07-10 | 2018-07-10 | Sublingual pharmaceutical composition |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3785698A4 (en) * | 2018-04-27 | 2022-01-19 | Beijing Tiantan Hospital Capital Medical University | Edaravone pharmaceutical composition |
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- 2018-07-10 CN CN201810748134.XA patent/CN110693882A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3785698A4 (en) * | 2018-04-27 | 2022-01-19 | Beijing Tiantan Hospital Capital Medical University | Edaravone pharmaceutical composition |
| US12016951B2 (en) | 2018-04-27 | 2024-06-25 | Beijing Tiantan Hospital, Capital Medical University | Edaravone pharmaceutical composition |
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Application publication date: 20200117 |