WO2018040989A1 - 依达拉奉与(+)-2-莰醇的舌下用药物组合物 - Google Patents

依达拉奉与(+)-2-莰醇的舌下用药物组合物 Download PDF

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WO2018040989A1
WO2018040989A1 PCT/CN2017/098620 CN2017098620W WO2018040989A1 WO 2018040989 A1 WO2018040989 A1 WO 2018040989A1 CN 2017098620 W CN2017098620 W CN 2017098620W WO 2018040989 A1 WO2018040989 A1 WO 2018040989A1
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edaravone
nonanol
pharmaceutical composition
sublingual
composition according
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PCT/CN2017/098620
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English (en)
French (fr)
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王毅军
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烟台益诺依生物医药科技有限公司
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Priority to EP17845291.8A priority Critical patent/EP3505161B1/en
Priority to CA3037089A priority patent/CA3037089C/en
Priority to CN201780048512.7A priority patent/CN109906077B/zh
Priority to AU2017317950A priority patent/AU2017317950B2/en
Priority to RU2019108605A priority patent/RU2720204C1/ru
Priority to KR1020197005273A priority patent/KR102216381B1/ko
Priority to JP2019530537A priority patent/JP6751475B2/ja
Priority to US16/326,470 priority patent/US11135199B2/en
Publication of WO2018040989A1 publication Critical patent/WO2018040989A1/zh
Priority to ZA2019/01866A priority patent/ZA201901866B/en

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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
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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    • 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
    • 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
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
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    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • 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

Definitions

  • the invention belongs to the technical field of medicine, and relates to a sublingual pharmaceutical composition of edaravone and (+)-2-nonanol and a preparation method thereof.
  • Edaravone (chemical name: 3-methyl-1-phenyl-2-pyrazol-5-one) is a marketed neuroprotective agent (Yakugaku Zasshi. 2004, 124(3): 99-111) .
  • edaravone has antioxidant activity, can significantly improve the symptoms of neurological deficits in cerebral ischemia-reperfusion animals, reduce infarct size, reduce the degree of brain damage, reduce brain edema, and inhibit lipid peroxidation in damaged brain tissue. .
  • (+)-2-nonanol is the main ingredient of the traditional Chinese medicine natural borneol.
  • the borneol has the functions of “returning to the sputum”, “fragrance to the curtain” and “taking the medicine up”, often used as “citing medicine” to increase other
  • the therapeutic effect of the drug; "Materia Medica” means that the borneol is "weak and weak, and the ambassador is effective.”
  • Animal experiments and in vitro experiments show that borneol has the effect of promoting drug permeability through the blood-brain barrier.
  • Cerebrovascular disease is an acute disease that needs to be quickly relieved, so injection is the preferred method of first aid.
  • the invention patent entitled "A pharmaceutical composition and its use in the preparation of a medicament for the treatment of cerebrovascular diseases" discloses a specific ratio composition of edaravone and (+)-2-nonanol injection.
  • the composition exhibits better pharmacological results than edaravone injection.
  • intramuscular or intravenous injection can cause pain and irritation at the injection site, requires medical personnel to operate, and also requires injectables.
  • the application is subject to certain medical restrictions and is not suitable for patients who are outside the hospital.
  • the sublingual preparation is directly absorbed by the sublingual mucosa.
  • the submucosal mucosa has a large surface area and strong penetrating ability, and a large number of capillaries under the mucosa are aggregated into the internal jugular vein.
  • the vena cava directly enters the blood circulation, and the drug is quickly absorbed after administration. It has fast onset, accurate quantitative and convenient use, and can avoid the first-pass effect of oral drugs. Compared with injections, sublingual tablets can greatly improve the convenience of medication and clinical patient compliance.
  • sublingual pharmaceutical compositions comprising edaravone and (+)-2-nonanol are not readily available.
  • the present inventors have found that common excipients do not produce acceptable sublingual tablets, or that the properties (stability, release rate, etc.) of the resulting sublingual tablets are not satisfactory.
  • It is an object of the present invention to provide a sublingual pharmaceutical composition comprising edaravone or a salt thereof and (+)-2-nonanol.
  • (+)-2-nonanol makes it difficult to stabilize the content of (+)-2-nonanol in solid preparations.
  • the drug of the sublingual tablet must be released quickly to reach a certain blood concentration. Play a therapeutic effect.
  • the inventors have unexpectedly discovered that the above problems can be effectively solved by using an excipient comprising a combination of mannitol and copovidone. Based on this finding, the present invention provides a sublingual pharmaceutical composition comprising edaravone or a salt thereof and (+)-2-nonanol, wherein (+)-2-nonanol is stable in content and pharmaceutically active The ingredients are quickly released and absorbed under the tongue.
  • a sublingual tablet comprising a composition of edaravone and (+)-2-nonanol, characterized by comprising an active ingredient edaravone or a salt thereof and (+)-2-nonanol, and pharmaceutically An acceptable adjuvant, said pharmaceutically acceptable excipient comprising an excipient selected from the group consisting of mannitol, lactose, dextran, cysteine, glycine, copovidone and betacyclodextrin One or more, preferably, the excipient comprises a combination of mannitol and copovidone.
  • mannitol and copovidone are contained as excipients in a mass ratio of 1:5 to 5:1; preferably 1:1 to 5:1.
  • the excipient comprises a combination of mannitol, copovidone and microcrystalline cellulose.
  • the mass ratio of the mannitol, copovidone and microcrystalline cellulose is (5 to 10): (1 to 5): (10 to 20).
  • the excipient comprises a combination of mannitol, copovidone and lactose.
  • the mass ratio of the mannitol, copovidone and lactose is (1 to 10): (1 to 5): (10 to 30).
  • the mass ratio of edaravone to (+)-2-nonanol in terms of free base is greater than 4 or less than 1, preferably, edaravone in terms of free base
  • the mass ratio of +)-2-nonanol is more than 4 and less than 10 or more than 0.1 and less than 1, and further preferably, the mass ratio of edaravone to (+)-2-nonanol is 5 in terms of free base.
  • the weight ratio of the (+)-2-nonanol to the excipient is 0.1 to 1, preferably, the weight ratio is 0.3 to 1, and more preferably, (+)-2-
  • the weight ratio of sterol to excipient is from 0.3 to 0.5.
  • the preparation method of the above-mentioned sublingual administration composition comprises the steps of dissolving (+)-2-nonanol in an ethanol solution, dissolving the excipient in an aqueous solution, and stirring the mixture, lyophilizing, sieving, adding Edaravone and other excipients are mixed evenly and compressed.
  • the sublingual administration composition has a blood concentration of edaravone of 10 to 8000 ng/mL and a blood concentration of (+)-2-nonanol of about 1 to 10 hours after administration of the unit preparation. ⁇ 200 ng/mL, preferably, the edaravone blood concentration reaches 50-5000 ng/mL, and the (+)-2-nonanol blood concentration reaches 2 in about 0.1 to 6 hours after the administration of the unit preparation. ⁇ 150 ng/mL.
  • Figure 1 is a dissolution profile of Examples 1 to 5.
  • Figure 2 is a dissolution profile of Examples 6 to 11.
  • Figure 3 is a dissolution profile of Examples 8, 12 to 14.
  • the invention discloses a sublingual administration preparation of edaravone and (+)-2-nonanol, and those skilled in the art can learn from the content of the invention, combine the principle of pharmacy, appropriately improve the process parameters or the prescription ratio to realize . It is to be noted that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included within the scope of the invention.
  • the application of the present invention has been described in terms of a preferred embodiment, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the spirit, scope and scope of the invention. The technique of the present invention is applied.
  • the edaravone mentioned in the examples is 3-methyl-1-phenyl-2-pyrazolin-5-one.
  • (+)-2-nonanol, edaravone, lactose, hypromellose, croscarmellose sodium, magnesium stearate are uniformly mixed and tableted.
  • (+)-2-nonanol, edaravone, lactose, hypromellose, croscarmellose sodium, magnesium stearate are uniformly mixed and tableted.
  • (+)-2-nonanol is dissolved in ethanol solution, betacyclodextrin is dissolved in aqueous solution, and the two are stirred and allowed to stand, freeze-dried, sieved, and added edaravone, lactose, hydroxypropyl Methylcellulose, croscarmellose sodium, magnesium stearate are uniformly mixed and compressed.
  • (+)-2-nonanol is dissolved in ethanol solution, betacyclodextrin is dissolved in aqueous solution, and the two are stirred and allowed to stand, freeze-dried, sieved, and added edaravone, lactose, hydroxypropyl Methylcellulose, croscarmellose sodium, magnesium stearate are uniformly mixed and compressed.
  • the preparation method comprises the following steps: dissolving (+)-2-nonanol in an ethanol solution, (+)-2-nonanol by weight of 5 times of mannitol, and a small amount of copolyvidone in an aqueous solution, and the two are stirred and allowed to stand, and frozen. Dry, sift, add edaravone, residual mannitol, copovidone, croscarmellose sodium, magnesium stearate, and mix well.
  • the preparation method comprises the following steps: dissolving (+)-2-nonanol in an ethanol solution, (+)-2-merol by weight three times of mannitol, and a small amount of copolyvidone in an aqueous solution, and the two are stirred and allowed to stand, and frozen. Dry, sift, add edaravone, residual mannitol, copovidone, croscarmellose sodium, magnesium stearate, and mix well.
  • (+)-2-nonanol is dissolved in an ethanol solution, mannitol, a small amount of copolyvidone is dissolved in an aqueous solution, and the two are stirred and allowed to stand, freeze-dried, sieved, and added to edaravone, lactose, Copolyvidone, cross-linking Sodium carboxymethylcellulose and magnesium stearate are uniformly mixed and compressed.
  • (+)-2-nonanol is dissolved in an ethanol solution, mannitol, a small amount of copolyvidone is dissolved in an aqueous solution, and the two are stirred and allowed to stand, freeze-dried, sieved, and added to edaravone, lactose, Copovidone, croscarmellose sodium, magnesium stearate are uniformly mixed and tableted.
  • the preparation method comprises the following steps: dissolving (+)-2-nonanol in an ethanol solution, (+)-2-nonanol by weight of 5 times of lactose, and a small amount of copolyvidone in an aqueous solution, and the two are stirred and allowed to stand, freeze-dried. After sieving, add edaravone, residual lactose, copovidone, croscarmellose sodium, magnesium stearate, and mix well.
  • Copolyvidone 8 Cross-linked carboxymethyl fiber 4 Magnesium stearate 0.8
  • the preparation method comprises the following steps: dissolving (+)-2-nonanol in an ethanol solution, (+)-2-nonanol in a weight of 1.25 times of lactose, and a small amount of copolyvidone in an aqueous solution, and the two are stirred and allowed to stand, freeze-dried. After sieving, add edaravone, residual lactose, copovidone, croscarmellose sodium, magnesium stearate, and mix well.
  • (+)-2-nonanol is dissolved in ethanol solution, mannitol, a small amount of copolyvidone is dissolved in an aqueous solution, and the two are combined and stirred, freeze-dried, sieved, and added to edaravone and microcrystals.
  • Cellulose, copovidone, croscarmellose sodium, magnesium stearate are uniformly mixed and tableted.
  • the preparation method comprises the following steps: dissolving (+)-2-nonanol in an ethanol solution, mannitol and copolyvidone in an aqueous solution, and the two are stirred and allowed to stand, freeze-dried, sieved, and added edaravone and microcrystalline fiber.
  • Carbohydrate The base cellulose sodium, silica, and magnesium stearate are uniformly mixed and tableted.
  • (+)-2-nonanol is dissolved in ethanol solution, mannitol, a small amount of copolyvidone is dissolved in an aqueous solution, and the two are combined and stirred, freeze-dried, sieved, and added to edaravone and microcrystals.
  • Cellulose, copovidone, croscarmellose sodium, silica, magnesium stearate are uniformly mixed and tableted.
  • Stability test results The appropriate amount of the samples of Examples 1-14 was taken, and the package was simulated. The samples were taken at 40 ° C and 60 ° C for 10 days, 30 days, and 90 days. The traits, contents, and related substances were determined. The results are as follows:
  • Dissolution test method take the test sample, according to the dissolution and release method of the Chinese Pharmacopoeia 2015 edition (fourth part 0931, the second method), with 900ml water as the dissolution medium (the examples 3, 4 are adopted) 250ml water is the dissolution medium), the rotation speed is 50rpm, according to the law, sampling at different time points, filtering through 0.8 ⁇ m filter membrane, taking the filtrate as the test solution; taking appropriate amount of edaravone reference substance, adding 20mmol/L Ammonium acetate / acetonitrile (80:20) was dissolved and diluted to about 0.02 mg / ml, ready for use. The UV absorbance of the test solution was measured at 254 nm, and the dissolution of the sample was calculated. The results are shown in Figures 1, 2 and 3.
  • Sublingual tablets were prepared according to the formulation ratio of Example 8, each tablet containing 5 mg of edaravone and 1 mg of sterol.
  • Dosage 16 mg/kg edaravone, 4 mg/kg (+)-2-nonanol, administration volume 8 mL/kg.
  • Blood Sampling time points of pulp and brain tissue samples 2 min, 15 min, 30 min, 1 h, 2.5 h, 5 h. At each time point, whole blood and brain tissue were collected simultaneously.
  • SD rats were given intravenous edaravone injection and sublingual administration of decyl alcohol in the sublingual homogenate.
  • the distribution of the sublingual tablets in plasma and brain tissue of SD rats showed that the bioavailability of edaravone and (+)-2-nonanol sublingual preparation was about 62.6%, edaravone; 51.6%, (+)-2-nonanol), bioavailability in the brain (28.5%, edaravone; 28.5%, (+)-2-nonanol), indicating sublingual administration of edaravone and sterol The bioavailability is high, and the sublingual administration conditions are met.
  • the sublingual tablets of edaravone and (+)-2-nonanol have good pharmacokinetic properties, high bioavailability, high brain permeability, and convenient use of sublingual tablets.
  • Sublingual tablets were prepared according to the prescription ratio of Example 8 in three specifications, respectively containing edaravone 0.67 mg And sterol 0.13mg (3mg/kg dose group); edaravone 2.01mg and sterol 0.39mg (9mg/kg dose group); edaravone 6mg and sterol 1.2mg (27mg/kg dose group) Medication).
  • a model of cerebral ischemia reperfusion in the middle cerebral artery occlusion (MCAO) was performed by internal carotid artery suture. After anesthesia with 7% hydrated trichloroacetaldehyde (6ml/kg), the prone position was fixed on the operating table, the skin was disinfected, the neck was cut open, and the right common carotid artery, external carotid artery and internal carotid artery were separated. The vagus nerve was gently removed, the external carotid artery was ligated and the carotid artery was advanced, and the pterygoid artery was ligated.
  • MCAO middle cerebral artery occlusion
  • the proximal common carotid artery was clamped, and the distal end of the ligature line of the external carotid artery was made into a mouth.
  • the nylon wire with an outer diameter of 0.285 mm was inserted into the internal carotid artery, and then inserted into the internal carotid artery. Slight resistance (about 20mm from the bifurcation), block all blood supply to the middle cerebral artery, 2.0h after right cerebral ischemia, gently pull out the nylon thread, restore blood supply for reperfusion, suture the skin, disinfect
  • the experimental animals were divided into three groups (3 mg/kg, 9 mg/kg, 27 mg/kg) of the sublingual tablets of the composition, the edaravone group (3 mg/kg) and the model group of the positive drug combination, and a total of 5 groups.
  • the animals were equally blindly assigned to each group.
  • the animals in the composition group were given sublingual tablets under the sublingual reperfusion, one piece per mouse, and the mouse mouth was fixed to prevent the tablets from falling out or sliding into the gastrointestinal tract until the tablets were completely absorbed; the positive drug group animals
  • the tail vein was administered once immediately after reperfusion, and the model group animals were given an equal volume of physiological saline.
  • the symptoms of neurological deficit were evaluated 24 hours after cerebral ischemia, and then the animals were sacrificed, brains were taken, stained, and photographed to determine the area of cerebral infarction.
  • Neurological symptoms were assessed using the modified Bederson 5 method.
  • the symptoms of neurological deficits in rats after cerebral ischemia were evaluated by a single-blind method.
  • the animals were grouped by the test designer and the subjects who scored the symptoms of neurological defects did not know the grouping of the animals. After the score was over, the scorer would The scores of the various markers were submitted to the designer, and the designer was unblinded to obtain a score for each animal of each test group.
  • the brain was decapitated, the olfactory bulb, the cerebellum and the lower brain stem were removed.
  • the blood surface of the brain was washed with physiological saline, and the surface residual water was removed.
  • the -20 ° C was placed for 20 min, and immediately after removal, The line of intersection of the line of sight is cut vertically downwards, and sliced every 2 mm backward.
  • the brain slices are incubated in 2% TTC dye solution (37 ° C for 90 min), the normal brain tissue is stained dark red, and the ischemic brain tissue is It was pale and washed with saline.
  • the brain slices were quickly arranged in a row from front to back, and the residual water traces on the surface were taken.
  • the photos were processed by image analysis software, and the corresponding volume of the left brain and the volume of the infarct were calculated according to the formula, and the percentage of infarcts was determined.
  • V t(A1+A2+A3+.........+An)
  • t is the slice thickness and A is the infarct size.
  • %I is the percentage of infarct volume
  • VC is the brain volume of the control side (left hemisphere)
  • VL is the volume of non-infarct area of the infarct side (right hemisphere).
  • the degree of neurological symptoms in each group of animals is shown in Table 1. Compared with the model group, the three sublingual doses of the composition (3, 9, 27 mg/kg) and the positive drug edaravone (3 mg/kg) were significant. Improve symptoms of neurological deficits.
  • Sublingual tablets were prepared according to the formulation ratio of Example 13, each tablet containing 5 mg of edaravone and 1 mg of sterol. 1.6 method
  • Dosage 16 mg/kg edaravone, 4 mg/kg (+)-2-nonanol, administration volume 8 mL/kg. Plasma and brain tissue samples were sampled at 2 min, 15 min, 30 min, 1 h, 2.5 h, 5 h. At each time point, whole blood and brain tissue were collected simultaneously.
  • SD rats were given intravenous edaravone injection and sublingual tablets in the brain homogenate Mean drug parameters.
  • SD rats were given intravenous edaravone injection and sublingual administration of decyl alcohol in the sublingual homogenate.
  • the distribution of the sublingual tablets in plasma and brain tissue of SD rats showed that the bioavailability of edaravone and (+)-2-nonol sublingual preparation was about 79.9%, edaravone; 60.1%, (+)-2-nonanol), bioavailability in the brain (30.1%, edaravone; 29.6%, (+)-2-nonanol), indicating sublingual administration of edaravone and sterol The bioavailability is high, and the sublingual administration conditions are met.
  • the sublingual tablets of edaravone and (+)-2-nonanol have good pharmacokinetic properties, high bioavailability, high brain permeability, and convenient use of sublingual tablets.
  • Sublingual tablets were prepared according to the prescription ratio of Example 13 in three specifications, containing edaravone 0.67 mg and sterol 0.13 mg (3 mg/kg dose group); edaravone 2.01 mg and sterol 0.39 mg (9 mg/kg dose group); edaravone 6 mg and sterol 1.2 mg (27 mg/kg dose group).
  • a model of cerebral ischemia reperfusion in the middle cerebral artery occlusion (MCAO) was performed by internal carotid artery suture. After anesthesia with 7% hydrated trichloroacetaldehyde (6ml/kg), the prone position was fixed on the operating table, the skin was disinfected, the neck was cut open, and the right common carotid artery, external carotid artery and internal carotid artery were separated. The vagus nerve was gently removed, the external carotid artery was ligated and the carotid artery was advanced, and the pterygoid artery was ligated.
  • MCAO middle cerebral artery occlusion
  • the proximal common carotid artery was clamped, and the distal end of the ligature line of the external carotid artery was made into a mouth.
  • the nylon wire with an outer diameter of 0.285 mm was inserted into the internal carotid artery, and then inserted into the internal carotid artery. Slight resistance (about 20mm from the bifurcation), block all blood supply to the middle cerebral artery, 2.0h after right cerebral ischemia, gently pull out the nylon thread, restore blood supply for reperfusion, suture the skin, disinfect
  • the experimental animals were divided into three groups (3 mg/kg, 9 mg/kg, 27 mg/kg) of the sublingual tablets of the composition, the edaravone group (3 mg/kg) and the model group of the positive drug combination, and a total of 5 groups.
  • the odds of animals were equally and blindly assigned to each group.
  • the animals in the composition group were given sublingual tablets under the sublingual reperfusion, one piece per mouse, and the mouse mouth was fixed to prevent the tablets from falling out or sliding into the gastrointestinal tract until the tablets were completely absorbed; the positive drug group animals
  • the tail vein was administered once immediately after reperfusion, and the model group animals were given an equal volume of physiological saline.
  • the symptoms of neurological deficit were evaluated 24 hours after cerebral ischemia, and then the animals were sacrificed, brains were taken, stained, and photographed to determine the area of cerebral infarction.
  • Neurological symptoms were assessed using the modified Bederson 5 method.
  • the symptoms of neurological deficits in rats after cerebral ischemia were evaluated by a single-blind method.
  • the animals were grouped by the test designer and the subjects who scored the symptoms of neurological defects did not know the grouping of the animals. After the score was over, the scorer would The scores of the various markers were submitted to the designer, and the designer was unblinded to obtain a score for each animal of each test group.
  • the brain was decapitated, the olfactory bulb, the cerebellum and the lower brain stem were removed.
  • the blood surface of the brain was washed with physiological saline, and the surface residual water was removed.
  • the -20 ° C was placed for 20 min, and immediately after removal, The line of intersection of the line of sight is cut vertically downwards, and sliced every 2 mm backward.
  • the brain slices are incubated in 2% TTC dye solution (37 ° C for 90 min), the normal brain tissue is stained dark red, and the ischemic brain tissue is It was pale and washed with saline.
  • the brain slices were quickly arranged in a row from front to back, and the residual water traces on the surface were taken.
  • the photos were processed by image analysis software, and the corresponding volume of the left brain and the volume of the infarct were calculated according to the formula, and the percentage of infarcts was determined.
  • V t(A1+A2+A3+.........+An)
  • t is the slice thickness and A is the infarct size.
  • %I is the percentage of infarct volume
  • VC is the brain volume of the control side (left hemisphere)
  • VL is the volume of non-infarct area of the infarct side (right hemisphere).
  • the degree of neurological symptoms in each group of animals is shown in Table 1. Compared with the model group, the three sublingual doses of the composition (3, 9, 27 mg/kg) and the positive drug edaravone (3 mg/kg) were significant. Improve symptoms of neurological deficits.

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Abstract

一种含有依达拉奉与(+)-2-莰醇的舌下片药物组合物及其制备方法。该舌下片药物组合物包含依达拉奉、(+)-2-莰醇、赋形剂、填充剂、粘合剂、崩解剂、润滑剂，其中赋形剂选自甘露醇、乳糖、右旋糖酐、半胱氨酸、甘氨酸、共聚维酮和倍他环糊精中的一种或几种。

Description

依达拉奉与(+)-2-莰醇的舌下用药物组合物 技术领域
本发明属于医药技术领域，涉及一种依达拉奉与(+)-2-莰醇的舌下用药物组合物及其制备方法。
背景技术
依达拉奉(化学名：3-甲基-1-苯基-2-吡唑啉-5-酮)是已上市脑神经保护剂(Yakugaku Zasshi.2004,124(3):99-111)。研究表明，依达拉奉具有抗氧化活性，能够显著地改善脑缺血再灌注动物的神经缺陷症状，缩小梗死面积，降低脑损伤程度，减轻脑水肿，抑制受损脑组织的脂质过氧化。
Figure PCTCN2017098620-appb-000001
(分子式C10H10N2O，分子量174.20)
(+)-2-莰醇是一味常用中药天然冰片的主要成分，冰片具有“回苏开窍”、“芳香走帘”、“引药上行”之功，常作“引药”，以增加其他药物的治疗效果；《本草衍义》指出冰片“独行则势弱，佐使则有功”。动物实验及离体实验表明：冰片具有促进药物透过血脑屏障的作用。
Figure PCTCN2017098620-appb-000002
(分子式C10H18O；分子量154.25)
脑血管病，特别是缺血性脑血管疾病属于急性疾病，需迅速解除病症，因此注射给药是急救的首选方法。名称为“一种药物组合物及其在制备治疗脑血管病药物中的应用”的发明专利(CN101848711A)，公开了依达拉奉和(+)-2-莰醇注射液特定比例组合物在制备治疗脑血管病，特别是缺血性脑血管病药物中的应用，该组合物相比依达拉奉注射液表现出了更好的药效结果。
然而，肌肉注射或静脉注射可以引起注射部位疼痛及剌激，需要有医护人员操作，还需注射用品等，应用上受到一定的医疗限制，并不适于院外发病的患者。
舌下用制剂是由舌下粘膜直接吸收，舌下粘膜表面积大，渗透能力强，且粘膜下有大量毛细血管汇总至颈内静脉，经上腔静脉直接进入血液循环，给药后药物迅速吸收，起效快、定量准确、使用方便，可避免口服药物的首过效应。相较于注射剂，舌下片剂可以极大提高用药的方便性和临床病人的依从性。
不过，包含依达拉奉和(+)-2-莰醇的舌下用药物组合物并不易于制得。本发明人发现，常见的赋形剂并不能制得合格的舌下片，或者所制得舌下片的性能(稳定性、释放速度等)并不令人满意。
因此，现有技术仍迫切需要一种包含依达拉奉和(+)-2-莰醇的具有满意的稳定性和释放速度的舌下用药物组合物。
发明内容
本发明的目的在于提供一种舌下用药物组合物，包括依达拉奉或其盐及(+)-2-莰醇。
(+)-2-莰醇的挥发性，使得(+)-2-莰醇在固体制剂中含量很难稳定，同时，舌下片的药物必须能快速释放，达到一定的血药浓度，才能发挥治疗效果。本发明人出乎意料地发现：采用包含甘露醇和共聚维酮组合的赋形剂，可以有效地解决上述问题。基于此发现，本发明提供了一种包含依达拉奉或其盐和(+)-2-莰醇的舌下用药物组合物，其中(+)-2-莰醇含量稳定，并且药物活性成分在舌下能快速释放并被吸收。
为了实现上述目的，本发明采用了以下技术方案：
一种含有依达拉奉与(+)-2-莰醇的组合物的舌下片，其特征在于含有活性成分依达拉奉或其盐与(+)-2-莰醇，以及药学上可接受的辅料，所述的药学上的辅料包括赋形剂，所述的赋形剂选自甘露醇、乳糖、右旋糖酐、半胱氨酸、甘氨酸、共聚维酮和倍他环糊精中的一种或几种，优选地，所述赋形剂包含甘露醇和共聚维酮的组合。
在本发明的优选的舌下给药组合物中，包含甘露醇和共聚维酮作为赋形剂，其质量比为1:5～5:1；优选为1:1～5:1。
在本发明的一些优选的实施方案中，所述赋形剂包含甘露醇、共聚维酮和微晶纤维素的组合。优选地，所述甘露醇、共聚维酮和微晶纤维素的质量比为(5～10)：(1～5)：(10～20)。
在本发明的另外一些优选的实施方案中，所述赋形剂包含甘露醇、共聚维酮和乳糖的组合。优选地，所述甘露醇、共聚维酮和乳糖的质量比为(1～10)： (1～5)：(10～30)。
上述舌下给药组合物中，以游离碱计的依达拉奉和(+)-2-莰醇的质量比大于4或小于1，优选的，以游离碱计的依达拉奉和(+)-2-莰醇的质量比大于4小于10或大于0.1小于1，再优选的，以游离碱计的依达拉奉和(+)-2-莰醇的质量比为5。
上述舌下给药组合物，所述的(+)-2-莰醇和赋形剂的重量比为0.1～1，优选的，重量比为0.3～1，再优选的，(+)-2-莰醇和赋形剂的重量比为0.3～0.5。
上述舌下给药组合物的制备方法含有如下步骤：将(+)-2-莰醇溶于乙醇溶液，赋形剂溶于水溶液中，两者合并搅拌静置，冷冻干燥，过筛，加入依达拉奉和其他辅料，混合均匀，压片。
上述舌下给药组合物，在每单位制剂给药后的大约0.1到10小时内，依达拉奉血药浓度达到10～8000ng/mL，(+)-2-莰醇血药浓度达到1～200ng/mL，优选的，在每单位制剂给药后的大约0.1到6小时内，依达拉奉血药浓度达到50～5000ng/mL，(+)-2-莰醇血药浓度达到2～150ng/mL。
附图说明
附图1是实施例1至5的溶出曲线。
附图2是实施例6至11的溶出曲线。
附图3是实施例8、12至14的溶出曲线。
具体实施方式
本发明公开了依达拉奉及(+)-2-莰醇的舌下给药制剂，本领域技术人员可以借鉴本发明的内容，结合药剂学原理，适当改进工艺参数或处方配比来实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明范围内。本发明的应用己经通过较好的实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
实施例中提及的依达拉奉是3-甲基-1-苯基-2-吡唑啉-5-酮。
以下通过实施例来进一步阐述本发明，但实施例不对本发明做任何限定。
实施例1
物料名称 用量(g)
依达拉奉 30
(+)-2-莰醇 1.5
乳糖 39.7
羟丙甲纤维素 4
交联羧甲基纤维 4
硬脂酸镁 0.8
制备方法：将(+)-2-莰醇、依达拉奉、乳糖、羟丙甲纤维素、交联羧甲基纤维素钠、硬脂酸镁混合均匀，压片。
实施例2
物料名称 用量(g)
依达拉奉 30
(+)-2-莰醇 2
乳糖 39.2
羟丙甲纤维素 4
交联羧甲基纤维 4
硬脂酸镁 0.8
制备方法：将(+)-2-莰醇、依达拉奉、乳糖、羟丙甲纤维素、交联羧甲基纤维素钠、硬脂酸镁混合均匀，压片。
实施例3
物料名称 用量(g)
依达拉奉 1.5
(+)-2-莰醇 30
乳糖 39.7
羟丙甲纤维素 4
交联羧甲基纤维 4
硬脂酸镁 0.8
制备方法：将(+)-2-莰醇、依达拉奉、乳糖、羟丙甲纤维素、交联羧甲基纤 维素钠、硬脂酸镁混合均匀，压片。
实施例4
物料名称 用量(g)
依达拉奉 6
(+)-2-莰醇 30
倍他环糊精 35.2
乳糖 10
羟丙甲纤维素 4
交联羧甲基纤维 4
硬脂酸镁 0.8
制备方法：将(+)-2-莰醇溶于乙醇溶液，倍他环糊精溶于水溶液中，两者合并搅拌静置，冷冻干燥，过筛，加入依达拉奉、乳糖、羟丙甲纤维素、交联羧甲基纤维素钠、硬脂酸镁混合均匀，压片。
实施例5
物料名称 用量(g)
依达拉奉 40
(+)-2-莰醇 8
倍他环糊精 23.2
乳糖 10
羟丙甲纤维素 4
交联羧甲基纤维 4
硬脂酸镁 0.8
制备方法：将(+)-2-莰醇溶于乙醇溶液，倍他环糊精溶于水溶液中，两者合并搅拌静置，冷冻干燥，过筛，加入依达拉奉、乳糖、羟丙甲纤维素、交联羧甲基纤维素钠、硬脂酸镁混合均匀，压片。
实施例6
物料名称 用量(g)
依达拉奉 30
(+)-2-莰醇 6
甘露醇 35.2
共聚维酮 4
交联羧甲基纤维 4
硬脂酸镁 0.8
制备方法：将(+)-2-莰醇溶于乙醇溶液，(+)-2-莰醇重量5倍量的甘露醇，少量共聚维酮溶于水溶液中，两者合并搅拌静置，冷冻干燥，过筛，加入依达拉奉、剩余甘露醇、共聚维酮、交联羧甲基纤维素钠、硬脂酸镁混合均匀，压片。
实施例7
物料名称 用量(g)
依达拉奉 50
(+)-2-莰醇 5
甘露醇 16.2
共聚维酮 4
交联羧甲基纤维 4
硬脂酸镁 0.8
制备方法：将(+)-2-莰醇溶于乙醇溶液，(+)-2-莰醇重量3倍量的甘露醇，少量共聚维酮溶于水溶液中，两者合并搅拌静置，冷冻干燥，过筛，加入依达拉奉、剩余甘露醇、共聚维酮、交联羧甲基纤维素钠、硬脂酸镁混合均匀，压片。
实施例8
物料名称 用量(g)
依达拉奉 30
(+)-2-莰醇 6
甘露醇 14
乳糖 22.2
共聚维酮 3
交联羧甲基纤维 4
硬脂酸镁 0.8
制备方法：将(+)-2-莰醇溶于乙醇溶液，甘露醇，少量共聚维酮溶于水溶液中，两者合并搅拌静置，冷冻干燥，过筛，加入依达拉奉、乳糖、共聚维酮、交联 羧甲基纤维素钠、硬脂酸镁混合均匀，压片。
实施例9
物料名称 用量(g)
依达拉奉 30
(+)-2-莰醇 6
甘露醇 6
乳糖 29.2
共聚维酮 4
交联羧甲基纤维 4
硬脂酸镁 0.8
制备方法：将(+)-2-莰醇溶于乙醇溶液，甘露醇，少量共聚维酮溶于水溶液中，两者合并搅拌静置，冷冻干燥，过筛，加入依达拉奉、乳糖、共聚维酮、交联羧甲基纤维素钠、硬脂酸镁混合均匀，压片。
实施例10
物料名称 用量(g)
依达拉奉 30
(+)-2-莰醇 6
乳糖 31.2
共聚维酮 8
交联羧甲基纤维 4
硬脂酸镁 0.8
制备方法：将(+)-2-莰醇溶于乙醇溶液，(+)-2-莰醇重量5倍量的乳糖，少量共聚维酮溶于水溶液中，两者合并搅拌静置，冷冻干燥，过筛，加入依达拉奉、剩余乳糖、共聚维酮、交联羧甲基纤维素钠、硬脂酸镁混合均匀，压片。
实施例11
物料名称 用量(g)
依达拉奉 12
(+)-2-莰醇 24
乳糖 31.2
共聚维酮 8
交联羧甲基纤维 4
硬脂酸镁 0.8
制备方法：将(+)-2-莰醇溶于乙醇溶液，(+)-2-莰醇重量1.25倍量的乳糖，少量共聚维酮溶于水溶液中，两者合并搅拌静置，冷冻干燥，过筛，加入依达拉奉、剩余乳糖、共聚维酮、交联羧甲基纤维素钠、硬脂酸镁混合均匀，压片。
实施例12
物料名称 用量(g)
依达拉奉 30
(+)-2-莰醇 6
甘露醇 14
微晶纤维素 22.2
共聚维酮 3
交联羧甲基纤维 4
硬脂酸镁 0.8
制备方法：将(+)-2-莰醇溶于乙醇溶液，甘露醇，少量共聚维酮溶于水溶液中，两者合并搅拌静置，冷冻干燥，过筛，加入依达拉奉、微晶纤维素、共聚维酮、交联羧甲基纤维素钠、硬脂酸镁混合均匀，压片。
实施例13
物料名称 用量(g)
依达拉奉 30
(+)-2-莰醇 6
甘露醇 6
微晶纤维素 16.2
共聚维酮 3
交联羧甲基纤维 7
二氧化硅 1.1
硬脂酸镁 0.7
制备方法：将(+)-2-莰醇溶于乙醇溶液，甘露醇，共聚维酮溶于水溶液中，两者合并搅拌静置，冷冻干燥，过筛，加入依达拉奉、微晶纤维素、交联羧甲 基纤维素钠、二氧化硅、硬脂酸镁混合均匀，压片。
实施例14
物料名称 用量(g)
依达拉奉 30
(+)-2-莰醇 6
甘露醇 14
微晶纤维素 11.2
共聚维酮 3
交联羧甲基纤维 4
二氧化硅 1.1
硬脂酸镁 0.7
制备方法：将(+)-2-莰醇溶于乙醇溶液，甘露醇，少量共聚维酮溶于水溶液中，两者合并搅拌静置，冷冻干燥，过筛，加入依达拉奉、微晶纤维素、共聚维酮、交联羧甲基纤维素钠、二氧化硅、硬脂酸镁混合均匀，压片。
实施例15
稳定性试验结果：取实施例1-14样品适量，模拟上市包装，在温度40℃和60℃条件下放置10天、30天、90天取样，对其性状、含量、有关物质进行了测定，结果见下表：
Figure PCTCN2017098620-appb-000003
Figure PCTCN2017098620-appb-000004
Figure PCTCN2017098620-appb-000005
Figure PCTCN2017098620-appb-000006
上述数据表明，实施例定性试验结果表明，各实施例4至14高温放置30 天，稳定性均良好。其中，实施例8、12、13、14高温放置90天，稳定性较好。
实施例16
溶出度测定试验方法：取供试品，照溶出度与释放度测定法《中国药典》2015版(第四部0931，第二法)，以900ml水为溶出介质(其中实施例3、4采用250ml水为溶出介质)，转速50rpm，依法操作，于不同的时间点分别取样，经0.8μm滤膜过滤，取续滤液作为供试品溶液；取依达拉奉对照品适量，加20mmol/L醋酸铵/乙腈(80:20)溶解并稀释至约0.02mg/ml，备用。于254nm条件下测定供试液紫外吸收度，计算样品溶出度，结果见附图1、2、3。
实施例17
依达拉奉舌下片在SD大鼠血浆和脑组织分布研究：
1.材料与方法
1.1实验动物
Sprague-Dawley(SD)大鼠，SPF级，雄性，体重180-200g。
来源：北京维通利华实验动物技术有限公司。
合格证编号：11400700138404。
许可证号：SCXK(京)2012-0001。
食物、给水：试验前禁食12h，给药后4h后提供食物，整个实验过程不禁水。给药及样品采集过程中观察并记录动物异常反应。
1.2受试药品
复方依达拉奉注射液：规格12.5mg/5mL(依达拉奉和(+)-2-莰醇分别为10mg/5mL，2.5mg/5mL)。
按实施例8处方比例制备舌下片剂，每片含依达拉奉5mg和莰醇1mg。
1.3方法
组1：静注给予复方依达拉奉注射液(N＝4)
给药剂量：16mg/kg依达拉奉，4mg/kg(+)-2-莰醇，给药体积8mL/kg。血 浆和脑组织样品采样时间点：2min，15min，30min，1h，2.5h，5h。在各时间点，同时采集全血和脑组织。
组2：舌下给予1片舌下片(N＝6)。
腹腔注射水合氯醛，使SD大鼠处于浅度麻醉状态，用50μL水润湿大鼠口腔，将药片塞入大鼠舌下，1片/只鼠，固定鼠嘴30min防止片剂掉出或滑入胃肠道。以塞入片剂到舌下的时间为0min时间点，之后分别在5min，15min，30min，1h，2.5h，5h采集全血和脑组织。
2.实验结果
SD大鼠静脉给予复方依达拉奉注射液和舌下片后血浆中依达拉奉各项平均药代参数。
  静注 舌下
Tmax(h) 0.033 2.5
Cmax(ng/mL) 58550 4793
AUC0-5h(h*ng/mL) 18179 15638
MRTlast(h) 0.59 2.06
F(％) / 62.6
SD大鼠静脉给予复方依达拉奉注射液和舌下片后脑匀浆中依达拉奉各项平均药代参数。
  静注 舌下
Tmax(h) 0.033 0.25
Cmax(ng/mL) 1405 55.3
AUC0-5h(h*ng/mL) 270 106
MRTlast(h) 0.20 1.18
F(％) / 28.5
SD大鼠静脉给予复方依达拉奉注射液和舌下片后血浆中莰醇各项平均药代参数。
Figure PCTCN2017098620-appb-000007
Figure PCTCN2017098620-appb-000008
SD大鼠静脉给予复方依达拉奉注射液和舌下给予舌下片后脑匀浆中莰醇各项平均药代参数。
  静注 舌下
Tmax(h) 0.033 0.5
Cmax(ng/mL) 5726 260
AUC0-5h(h*ng/mL) 1686 529
MRTlast(h) 0.34 1.31
F(％) / 28.5
该舌下片在SD大鼠血浆和脑组织分布研究结果显示：依达拉奉与(+)-2-莰醇舌下制剂，生物利用度约(62.6％，依达拉奉；51.6％，(+)-2-莰醇)，脑内生物利用度约(28.5％，依达拉奉；28.5％，(+)-2-莰醇)，表明舌下给药依达拉奉和莰醇生物利用度均较高，满足舌下给药条件。
依达拉奉和(+)-2-莰醇的舌下片具有较好的药代动力学性质，生物利用度高，脑通透率高；同时具有舌下片使用方便等优点。
实施例18
舌下片给药对局灶性脑缺血再灌损伤的保护作用
1材料和方法
1.1实验动物
Sprague-Dawley(SD)大鼠，雄性，清洁级，体重260-280g
1.2受试药品
按实施例8处方比例制备舌下片剂，共三个规格，分别含依达拉奉0.67mg 和莰醇0.13mg(3mg/kg剂量组用药)；依达拉奉2.01mg和莰醇0.39mg(9mg/kg剂量组用药)；依达拉奉6mg和莰醇1.2mg(27mg/kg剂量组用药)。
复方依达拉奉注射液，规格：5mL:12.5mg，南京先声东元制药有限公司生产
1.3实验方法
1.3.1局灶性脑缺血再灌模型的制备
采用颈内动脉线栓法制备大脑中动脉阻塞(Middle cerebral artery occlusion,MCAO)脑缺血再灌注模型。动物用7％水合三氯乙醛(6ml/kg)麻醉后，俯卧位固定于手术台上，消毒皮肤，颈部正中切开，分离右侧颈总动脉、颈外动脉、颈内动脉，轻轻剥离迷走神经，结扎并剪断颈外动脉，循颈内动脉向前，结扎翼腭动脉。夹闭颈总动脉近心端，从颈外动脉的结扎线的远端作一切口，插入外径为0.285mm的尼龙线，进过颈总动脉分叉进入颈内动脉，然后徐徐插入至有轻微阻力为止(自分叉处约20mm)，阻断大脑中动脉的所有血供，右侧脑缺血2.0h后，轻轻拔出尼龙线，恢复血供进行再灌注，缝合皮肤，消毒
1.3.2动物分组与给药
实验动物分为组合物舌下片3个剂量组(3mg/kg、9mg/kg、27mg/kg)、阳性药复方依达拉奉组(3mg/kg)及模型组，共5组。制备脑缺血模型后，将动物机率均等单盲分配至各组。组合物组动物于再灌注即时舌下给于相应规格舌下片，每鼠1片，固定鼠嘴，防止片剂掉出或滑入胃肠道，待药片完全被吸收为止；阳性药组动物于再灌注后立即尾静脉给药1次，模型组动物给于等体积的生理盐水。脑缺血后24小时评价神经缺陷症状，而后处死动物，取脑，染色，拍照测定脑梗死面积。
1.3.3神经缺陷症状评分及脑梗死面积的测定
采用改良Bederson 5分制法进行神经缺陷症状评价。采用单盲法评价脑缺血后大鼠的神经缺陷症状，即由试验设计者将动物按组标记，对神经缺陷症状进行评分的试验者不知道动物的分组情况，评分结束后，评分者将各种标记的评分结果呈交设计者，由设计者揭盲，获得各试验组每只动物的评分。
Figure PCTCN2017098620-appb-000009
脑梗死程度的测定，动物处死后，断头取脑，去除嗅球、小脑和低位脑干，用生理盐水冲洗大脑表面血迹，吸去表面残留水迹，于－20℃放置20min，取出后立即于视线交叉平面垂直向下作冠状切面，并向后每隔2mm切一片，将脑片置于2％TTC染液中孵育(37℃90min)，正常脑组织染成深红色，缺血脑组织则呈苍白色，用生理盐水冲洗后，迅速将脑片从前向后按顺序排成一排，吸干表面残留水迹，拍照。
照片用图像分析软件处理，根据公式计算左脑相应的体积以及梗死灶体积，求出梗死灶百分比。
梗死体积计算法：
V＝t(A1+A2+A3+………+An)
t为切片厚度，A为梗死面积。
％I＝100％×(VC-VL)/VC
％I为梗死体积百分比，VC为对照侧(左脑半球)脑体积，VL为梗死侧(右脑半球)非梗死区域体积。
2实验结果
2.1对神经缺陷症状的影响
各组动物神经缺陷症状的程度见表1，与模型组相比，组合物舌下3个剂量(3、9、27mg/kg)及阳性药复方依达拉奉(3mg/kg)均能显著改善神经缺陷症状。
表3.依达拉奉与(+)-2-莰醇复方舌下用药对神经缺陷症状的影响
Figure PCTCN2017098620-appb-000010
X±SD。与模型组相比，*p<0.05，**p<0.01
2.2对脑梗塞面积的影响
对脑梗塞面积的影响见表2，与模型组相比，组合物舌下3个剂量(3、9、27mg/kg)及阳性药复方依达拉奉均能显著减小动物缺血再灌后脑梗塞面积。
表2依达拉奉与(+)-2-莰醇复方舌下用药对脑梗面积的影响
组别 动物数 脑梗面积(％)
模型组 12 35.1±11.5
复方依达拉奉组 13 22.9±13.0*
舌下片(0.8mg) 14 24.0±10.0*
舌下片(2.4mg) 12 22.0±11.4*
舌下片(7.2mg) 13 20.7±13.1**
X±SD，与模型组相比，*p<0.05，**p<0.01
实施例19
依达拉奉舌下片在SD大鼠血浆和脑组织分布研究：
3.材料与方法
1.4实验动物
Sprague-Dawley(SD)大鼠，SPF级，雄性，体重180-200g。
来源：北京维通利华实验动物技术有限公司。
合格证编号：11400700138404。
许可证号：SCXK(京)2012-0001。
食物、给水：试验前禁食12h，给药后4h后提供食物，整个实验过程不禁水。给药及样品采集过程中观察并记录动物异常反应。
1.5受试药品
复方依达拉奉注射液：规格12.5mg/5mL(依达拉奉和(+)-2-莰醇分别为10mg/5mL，2.5mg/5mL)。
按实施例13处方比例制备舌下片剂，每片含依达拉奉5mg和莰醇1mg。1.6方法
组1：静注给予复方依达拉奉注射液(N＝4)
给药剂量：16mg/kg依达拉奉，4mg/kg(+)-2-莰醇，给药体积8mL/kg。血浆和脑组织样品采样时间点：2min，15min，30min，1h，2.5h，5h。在各时间点，同时采集全血和脑组织。
组2：舌下给予1片舌下片(N＝6)。
腹腔注射水合氯醛，使SD大鼠处于浅度麻醉状态，用50μL水润湿大鼠口腔，将药片塞入大鼠舌下，1片/只鼠，固定鼠嘴30min防止片剂掉出或滑入胃肠道。以塞入片剂到舌下的时间为0min时间点，之后分别在5min，15min，30min，1h，2.5h，5h采集全血和脑组织。
4.实验结果
SD大鼠静脉给予复方依达拉奉注射液和舌下片后血浆中依达拉奉各项平均药代参数。
  静注 舌下
Tmax(h) 0.032 0.5
Cmax(ng/mL) 56370 5875
AUC0-5h(h*ng/mL) 16038 17427
MRTlast(h) 0.59 2.63
F(％) / 79.9
SD大鼠静脉给予复方依达拉奉注射液和舌下片后脑匀浆中依达拉奉各项平 均药代参数。
  静注 舌下
Tmax(h) 0.032 0.25
Cmax(ng/mL) 1398 59.2
AUC0-5h(h*ng/mL) 255 110
MRTlast(h) 0.20 1.16
F(％) / 30.1
SD大鼠静脉给予复方依达拉奉注射液和舌下片后血浆中莰醇各项平均药代参数。
  静注 舌下
Tmax(h) 0.032 1.00
Cmax(ng/mL) 1571 114
AUC0-5h(h*ng/mL) 593 392
MRTlast(h) 0.63 1.93
F(％) / 60.1
SD大鼠静脉给予复方依达拉奉注射液和舌下给予舌下片后脑匀浆中莰醇各项平均药代参数。
  静注 舌下
Tmax(h) 0.032 0.5
Cmax(ng/mL) 5430 273
AUC0-5h(h*ng/mL) 1729 541
MRTlast(h) 0.34 1.30
F(％) / 29.6
该舌下片在SD大鼠血浆和脑组织分布研究结果显示：依达拉奉与(+)-2-莰醇舌下制剂，生物利用度约(79.9％，依达拉奉；60.1％，(+)-2-莰醇)，脑内生物利用度约(30.1％，依达拉奉；29.6％，(+)-2-莰醇)，表明舌下给药依达拉奉和莰醇生物利用度均较高，满足舌下给药条件。
依达拉奉和(+)-2-莰醇的舌下片具有较好的药代动力学性质，生物利用度高，脑通透率高；同时具有舌下片使用方便等优点。
实施例20
舌下片给药对局灶性脑缺血再灌损伤的保护作用
1材料和方法
1.1实验动物
Sprague-Dawley(SD)大鼠，雄性，清洁级，体重260-280g
1.2受试药品
按实施例13处方比例制备舌下片剂，共三个规格，分别含依达拉奉0.67mg和莰醇0.13mg(3mg/kg剂量组用药)；依达拉奉2.01mg和莰醇0.39mg(9mg/kg剂量组用药)；依达拉奉6mg和莰醇1.2mg(27mg/kg剂量组用药)。
复方依达拉奉注射液，规格：5mL:12.5mg，南京先声东元制药有限公司生产
1.3实验方法
1.3.1局灶性脑缺血再灌模型的制备
采用颈内动脉线栓法制备大脑中动脉阻塞(Middle cerebral artery occlusion,MCAO)脑缺血再灌注模型。动物用7％水合三氯乙醛(6ml/kg)麻醉后，俯卧位固定于手术台上，消毒皮肤，颈部正中切开，分离右侧颈总动脉、颈外动脉、颈内动脉，轻轻剥离迷走神经，结扎并剪断颈外动脉，循颈内动脉向前，结扎翼腭动脉。夹闭颈总动脉近心端，从颈外动脉的结扎线的远端作一切口，插入外径为0.285mm的尼龙线，进过颈总动脉分叉进入颈内动脉，然后徐徐插入至有轻微阻力为止(自分叉处约20mm)，阻断大脑中动脉的所有血供，右侧脑缺血2.0h后，轻轻拔出尼龙线，恢复血供进行再灌注，缝合皮肤，消毒
1.3.2动物分组与给药
实验动物分为组合物舌下片3个剂量组(3mg/kg、9mg/kg、27mg/kg)、阳性药复方依达拉奉组(3mg/kg)及模型组，共5组。制备脑缺血模型后，将 动物机率均等单盲分配至各组。组合物组动物于再灌注即时舌下给于相应规格舌下片，每鼠1片，固定鼠嘴，防止片剂掉出或滑入胃肠道，待药片完全被吸收为止；阳性药组动物于再灌注后立即尾静脉给药1次，模型组动物给于等体积的生理盐水。脑缺血后24小时评价神经缺陷症状，而后处死动物，取脑，染色，拍照测定脑梗死面积。
1.3.3神经缺陷症状评分及脑梗死面积的测定
采用改良Bederson 5分制法进行神经缺陷症状评价。采用单盲法评价脑缺血后大鼠的神经缺陷症状，即由试验设计者将动物按组标记，对神经缺陷症状进行评分的试验者不知道动物的分组情况，评分结束后，评分者将各种标记的评分结果呈交设计者，由设计者揭盲，获得各试验组每只动物的评分。
Figure PCTCN2017098620-appb-000011
脑梗死程度的测定，动物处死后，断头取脑，去除嗅球、小脑和低位脑干，用生理盐水冲洗大脑表面血迹，吸去表面残留水迹，于－20℃放置20min，取出后立即于视线交叉平面垂直向下作冠状切面，并向后每隔2mm切一片，将脑片置于2％TTC染液中孵育(37℃90min)，正常脑组织染成深红色，缺血脑组织则呈苍白色，用生理盐水冲洗后，迅速将脑片从前向后按顺序排成一排，吸干表面残留水迹，拍照。
照片用图像分析软件处理，根据公式计算左脑相应的体积以及梗死灶体积，求出梗死灶百分比。
梗死体积计算法：
V＝t(A1+A2+A3+………+An)
t为切片厚度，A为梗死面积。
％I＝100％×(VC-VL)/VC
％I为梗死体积百分比，VC为对照侧(左脑半球)脑体积，VL为梗死侧(右脑半球)非梗死区域体积。
2实验结果
2.1对神经缺陷症状的影响
各组动物神经缺陷症状的程度见表1，与模型组相比，组合物舌下3个剂量(3、9、27mg/kg)及阳性药复方依达拉奉(3mg/kg)均能显著改善神经缺陷症状。
表3.依达拉奉与(+)-2-莰醇复方舌下用药对神经缺陷症状的影响
Figure PCTCN2017098620-appb-000012
X±SD。与模型组相比，*p<0.05，**p<0.01
2.2对脑梗塞面积的影响
对脑梗塞面积的影响见表2，与模型组相比，组合物舌下3个剂量(3、9、27mg/kg)及阳性药复方依达拉奉均能显著减小动物缺血再灌后脑梗塞面积。
表2依达拉奉与(+)-2-莰醇复方舌下用药对脑梗面积的影响
组别 动物数 脑梗面积(％)
模型组 11 37.2±12.3
复方依达拉奉组 12 21.6±12.5*
舌下片(0.8mg) 14 23.4±9.3*
舌下片(2.4mg) 14 21.3±8.5*
舌下片(7.2mg) 13 19.8±10.1**
X±SD，与模型组相比，*p<0.05，**p<0.01
实验数据表明，本发明的舌下片能达到与注射剂相当的药效。

Claims (11)

  1. 一种含有依达拉奉与(+)-2-莰醇的舌下片用药物组合物，其包含药学上可接受的辅料，所述的药学上的辅料包括赋形剂，其中所述赋形剂包含选自甘露醇、乳糖、右旋糖酐、半胱氨酸、甘氨酸、共聚维酮和倍他环糊精中的一种或几种的赋形剂，优选包含选自甘露醇和共聚维酮的赋形剂。
  2. 根据权利要求1所述的药物组合物，其包含质量比为1:5～5:1的甘露醇和共聚维酮作为赋形剂。
  3. 根据权利要求2所述的药物组合物，其中甘露醇和共聚维酮的质量比为1:1～5:1。
  4. 根据权利要求1至3中任一项所述的药物组合物，其中以游离碱计的依达拉奉和(+)-2-莰醇的质量比大于4小于10或大于0.1小于1。
  5. 根据权利要求1至4中任一项所述的药物组合物，其中以游离碱计的依达拉奉和(+)-2-莰醇的质量比为5:1。
  6. 根据权利要求1至5中任一项所述的药物组合物，其中所述(+)-2-莰醇和赋形剂的重量比为0.1:1～1:1。
  7. 根据权利要求1至5中任一项所述的药物组合物，其中所述(+)-2-莰醇和赋形剂的重量比为0.3:1～1:1。
  8. 根据权利要求1至7中任一项所述的药物组合物，其中所述药物组合物为舌下片的形式。
  9. 制备根据权利要求8所述的药物组合物的方法，包括如下步骤：将(+)-2-莰醇溶于有机溶液中，将赋形剂溶于水溶液中，两者合并搅拌静置，冷冻干燥，过筛，加入依达拉奉、填充剂、粘合剂、崩解剂、润滑剂混合均匀，压片。
  10. 根据权利要求8所述的药物组合物，其中在每单位舌下片给予患者后的大约0.1到10小时内，依达拉奉血药浓度达到10～8000ng/mL，(+)-2-莰醇血药浓度达到1～200ng/mL。
  11. 根据权利要求8所述的药物组合物，其中在每单位舌下片给药后的大约0.1到6小时内，依达拉奉血药浓度达到50～5000ng/mL，(+)-2-莰醇血药浓度达到2～150ng/mL。
PCT/CN2017/098620 2016-08-29 2017-08-23 依达拉奉与(+)-2-莰醇的舌下用药物组合物 WO2018040989A1 (zh)

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