WO2023216429A1 - Comprimé adhésif buccal de lumbrokinase, son procédé de préparation et son utilisation - Google Patents

Comprimé adhésif buccal de lumbrokinase, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2023216429A1
WO2023216429A1 PCT/CN2022/108675 CN2022108675W WO2023216429A1 WO 2023216429 A1 WO2023216429 A1 WO 2023216429A1 CN 2022108675 W CN2022108675 W CN 2022108675W WO 2023216429 A1 WO2023216429 A1 WO 2023216429A1
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lumbrokinase
parts
cyclodextrin
oral adhesive
oral
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PCT/CN2022/108675
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English (en)
Chinese (zh)
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管悦琴
孙盛华
王秀兰
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广西纯正堂制药有限公司
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/484—Plasmin (3.4.21.7)
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • 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
    • A61K9/2013—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
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21007—Plasmin (3.4.21.7), i.e. fibrinolysin

Definitions

  • This application relates to the field of pharmaceutical technology, specifically to a lumbrokinase oral adhesive tablet and its preparation method and application.
  • Stroke is a type of cerebrovascular disease that occurs rapidly due to the rupture or blockage of blood vessels supplying blood to the brain and causes corresponding brain functional defects.
  • the main clinical symptoms are hemiplegia, aphasia, coma, etc. It can be divided into hemorrhagic diseases according to pathological factors. and ischemic categories.
  • Western medicine treatments for ischemic stroke mainly include comprehensive medical treatment, anti-cerebral edema and reduction of intracranial hypertension, improvement of cerebral blood circulation, neuroprotective agents, surgical treatment, endovascular interventional treatment and rehabilitation treatment. However, these methods do not really focus on the problem of ischemic stroke itself.
  • aspirin was approved by the US FDA as an antiplatelet drug.
  • As the first and most widely used antiplatelet drug in clinical practice aspirin is considered to be the primary and secondary prevention and acute treatment of ischemic stroke. Indispensable medicine. And multiple studies have shown that it can effectively reduce the incidence of vascular events, reinfarction rate, NIHSS score and mRS score in the secondary prevention of ischemic stroke. With the extensive and in-depth clinical use and various studies, it has been found that aspirin mainly has the following three limitations: its efficacy in reducing the incidence of vascular events, reinfarction rate and neurological damage needs to be improved. Studies have shown that aspirin is suitable for medium-risk patients.
  • One of the purposes of the embodiments of the present application is to provide a lumbrokinase oral adhesive tablet and a preparation method thereof, as well as a drug for treating ischemic stroke, aiming to solve the existing problems of treating ischemic stroke to a certain extent. Drug treatment is ineffective and slow, making it difficult to meet the needs of rescue treatment for acute stroke.
  • a method for preparing lumbrokinase oral adhesive tablets which is characterized in that it includes the following preparation steps:
  • the mixture is mixed with 40 to 160 parts of diluent I, 40 to 160 parts of dry adhesive, 60 to 240 parts of cross-linked polymer, and 60 to 240 parts of diluent II, and then tableted. , to obtain lumbrokinase oral adhesive tablets.
  • a lumbrokinase oral adhesive tablet which is characterized in that the lumbrokinase oral adhesive tablet includes raw material components: 8 to 32 parts of lumbrokinase, 40 to 160 parts of diluent I, and 60 to 240 parts of diluent II. , 60 to 240 parts of cross-linked polymer, 40 to 160 parts of dry adhesive, 0.6 to 4 parts of ⁇ -cyclodextrin derivatives, 4 to 16 parts of transdermal absorption accelerator, 2 to 8 parts of glidant, 2 to 8 parts of lubricant and 2 to 8 parts of flavoring agent.
  • an application of a lumbrokinase oral adhesive sheet is provided, which is characterized in that the lumbrokinase oral adhesive sheet prepared by the above method, or the above-mentioned lumbrokinase oral adhesive sheet, is applied to the oral mucosa of the patient.
  • the beneficial effects of the preparation method of lumbrokinase oral adhesive tablets are: the process is simple and suitable for industrial large-scale production and application, making the quality and efficacy of the prepared lumbrokinase oral adhesive tablets more stable and reliable, and the product's All indicators meet or even exceed national drug standards, and at the same time, the stability of the active ingredient lumbrokinase can be improved.
  • the prepared lumbrokinase oral adhesive tablets have the synergistic effect of each raw material component.
  • the lumbrokinase oral adhesive tablets have antipyretic, sedative, anticonvulsant, thrombolytic, anticoagulant, and platelet-lowering effects on the nerve, blood, and circulatory systems.
  • the route of administration is mucosal transdermal administration. Compared with the original enteric-coated preparations, the disintegration and dissolution time of enteric-coated tablets or capsules is omitted, and it can be quickly absorbed directly into the bloodstream from the oral mucosa. Enters the cerebral blood vessels and quickly relieves the ischemic state of the cerebral blood vessels, especially suitable for rescue treatment of acute stroke.
  • the beneficial effects of the lumbrokinase oral adhesive tablets are: including 8 to 32 parts of raw material components lumbrokinase, 40 to 160 parts of diluent I, 60 to 240 parts of diluent II, and 60 to 240 parts of cross-linked polymer.
  • ⁇ -cyclodextrin derivatives can form inclusion complexes with lumbrokinase, which can mask the odor of lumbrokinase and prevent lumbrokinase from being affected by light, oxygen, heat and certain environmental factors, which is beneficial to enhance the drug Stability can extend the efficacy and shelf life of drugs, and can also increase the solubility and dissolution rate of drugs.
  • the lumbrokinase oral adhesive tablets can stably adhere to the mucosal surface in the oral cavity.
  • the administration route of lumbrokinase oral adhesive tablets is mucosal transdermal administration through transdermal absorption enhancers and other components.
  • the disintegration and dissolution time of enteric-coated tablets or capsules is omitted, and the It is quickly absorbed into the bloodstream directly from the oral mucosa, quickly enters the cerebral blood vessels, and quickly relieves the ischemic state of the cerebral blood vessels. It is especially suitable for the rescue treatment of acute stroke.
  • the beneficial effects of the application of the lumbrokinase oral adhesive tablets are: the above-mentioned lumbrokinase oral adhesive tablets can be directly applied to the patient's oral mucosa, directly absorbed into the bloodstream by the oral mucosa, and quickly enter the cerebral blood vessels. It alleviates the ischemic state of cerebral blood vessels. Compared with the original enteric-coated preparations, it omits the disintegration and dissolution time of enteric-coated tablets or capsules, and is especially suitable for the rescue treatment of acute stroke.
  • Figure 1 is a schematic flow chart of the preparation method of lumbrokinase oral adhesive tablets provided by the embodiment of the present application;
  • Figure 2 is a schematic structural diagram of a device for measuring adhesion force provided by an embodiment of the present application.
  • a and/or B can mean: A exists alone, A and B exist simultaneously, and B exists alone. Condition. Where A and B can be singular or plural.
  • the character "/" generally indicates that the related objects are in an "or" relationship.
  • At least one refers to one or more
  • plural refers to two or more.
  • At least one of the following” or similar expressions thereof refers to any combination of these items, including any combination of a single item (items) or a plurality of items (items).
  • at least one of a, b, or c can mean: a, b, c, a-b (that is, a and b), a-c, b-c, or a-b-c, where a, b, and c may be single or multiple respectively.
  • the size of the sequence numbers of the above-mentioned processes does not mean the order of execution. Some or all steps can be executed in parallel or one after another. The execution order of each process should be based on its function and order. The internal logic is determined and should not constitute any limitation on the implementation process of the embodiments of the present application.
  • weights of relevant components mentioned in the description of the embodiments of the present application may not only refer to the specific content of each component, but also represent the proportional relationship of weight between the components. Therefore, as long as the relevant components are combined according to the description of the embodiments of the present application, Any scaling up or down of the content is within the scope disclosed in the examples of this application.
  • the mass in the description of the embodiments of this application may be mass units well known in the chemical industry such as ⁇ g, mg, g, kg, etc.
  • first and second are only used for descriptive purposes to distinguish objects such as substances from each other, and cannot be understood as indicating or implying relative importance or implicitly indicating the quantity of indicated technical features.
  • first XX may also be called the second XX
  • second XX may also be called the first XX. Therefore, features defined as “first” and “second” may explicitly or implicitly include one or more of these features.
  • the first aspect of the embodiment of the present application provides a method for preparing lumbrokinase oral adhesive tablets, which includes the following preparation steps:
  • the preparation method of lumbrokinase oral adhesive tablets includes dissolving the ⁇ -cyclodextrin derivative into a solvent and then adding lumbrokinase for inclusion treatment to obtain a lumbrokinase cyclodextrin inclusion complex; and then Then, the lubricant, glidant, flavoring agent, transdermal absorption accelerator and lumbrokinase cyclodextrin inclusion complex are mixed to make each raw material component evenly distributed to form a mixture.
  • the mixture is then mixed with diluent I, dry adhesive, cross-linked polymer, and diluent II to form a uniformly dispersed and stable mixed material, and then tableted to obtain lumbrokinase oral adhesive tablets.
  • the preparation method of lumbrokinase oral adhesive tablets in the embodiment of the present application has a simple process and is suitable for industrial large-scale production and application.
  • the quality and efficacy of the prepared lumbrokinase oral adhesive tablets are more stable and reliable, and the various indicators of the product reach or even exceed It complies with national drug standards and can improve the stability of the active ingredient lumbrokinase.
  • the prepared lumbrokinase oral adhesive tablets have the synergistic effect of each raw material component.
  • the lumbrokinase oral adhesive tablets have antipyretic, sedative, anticonvulsant, thrombolytic, anticoagulant, and platelet-lowering effects on the nerve, blood, and circulatory systems. It can reduce blood viscosity, reduce platelet aggregation, improve microcirculation, and has good thrombolytic and anticoagulant effects in vivo and in vitro with few adverse reactions. It can improve cerebral blood circulation and protect nerve function.
  • the route of administration is mucosal transdermal administration. Compared with the original enteric-coated preparations, the disintegration and dissolution time of enteric-coated tablets or capsules is omitted, and it can be quickly absorbed directly into the bloodstream from the oral mucosa. Enters the cerebral blood vessels and quickly relieves the ischemic state of the cerebral blood vessels, especially suitable for rescue treatment of acute stroke.
  • ⁇ -cyclodextrin derivatives are dissolved into a solvent to prepare a ⁇ -cyclodextrin derivative solution, and then 8 to 32 parts of lumbrokinase are added. Inclusion processing.
  • the ⁇ -cyclodextrin used in the embodiments of the present application is mainly used to increase the stability of the drug, prevent oxidation and decomposition of the drug, improve the dissolution and bioavailability of the drug, reduce the toxic and side effects of the drug, and mask the odor and smell of the drug. gas.
  • cyclodextrin since the molecular structure of cyclodextrin is composed of more than 6 glucoses connected through ⁇ -1,4 glycosidic bonds, it is barrel-shaped. A hydrophobic cavity is formed in the barrel, and lumbrokinase is absorbed into the cavity to form stable non-covalent complexes and inclusion complexes. Lumbrokinase is protected from the effects of light, oxygen, heat and certain environmental factors due to the inclusion of cyclodextrin, which is beneficial to enhancing drug stability and extending drug efficacy and shelf life.
  • the cyclodextrin inclusion complex is equivalent to a molecular capsule, and the lumbrokinase drug molecules are separated and dispersed in the oligosaccharide skeleton, so it can also increase the solubility and dissolution rate of the drug.
  • the ratio of ⁇ -cyclodextrin derivatives and lumbrokinase in the embodiments of the present application not only ensures the inclusion effect of cyclodextrin on lumbrokinase, but also ensures the content of the active ingredient of lumbrokinase in the prepared lumbrokinase oral adhesive tablets, thereby ensuring Ensure the efficacy of lumbrokinase oral adhesive tablets.
  • the mass ratio of ⁇ -cyclodextrin derivatives to lumbrokinase is 1: (6.5-26.5); the ⁇ -cyclodextrin derivatives in this ratio have better inclusion rates and lumbrokinase. Inclusion stability.
  • the mass ratio of ⁇ -cyclodextrin derivatives to lumbrokinase includes but is not limited to 1:(7 ⁇ 26), or 1:(8 ⁇ 23), or 1:(10 ⁇ 20) ), or 1: (12 ⁇ 18), or 1: (15 ⁇ 16), etc.
  • the step of inclusion treatment includes: dissolving the ⁇ -cyclodextrin derivative into an alcohol solution to fully dissolve it, and then adding lumbrokinase at a temperature of 20 to 80° C. and a rotation speed of 8000 to 12000 r/ After inclusion for 60 to 120 minutes under the conditions of 60 to 120 minutes, the lumbrokinase is fully included in the cyclodextrin, refrigerated until crystallization precipitates, and the lumbrokinase cyclodextrin inclusion complex is separated.
  • the separation step includes isolating the crystals through filtration such as suction filtration, then washing the crystals thoroughly with absolute ethanol, and then drying the crystals under vacuum to obtain the lumbrokinase cyclodextrin inclusion complex.
  • the ⁇ -cyclodextrin derivative is dissolved into an alcohol solution to fully dissolve it and form a saturated solution, which is more conducive to the subsequent inclusion and crystallization of lumbrokinase and improves the preparation efficiency.
  • the temperature of the inclusion treatment is 20-60°C, specifically 40°C; the rotation speed is 10000-12000 r/min; the inclusion time is 80-120 min, etc.
  • the ⁇ -cyclodextrin derivative is dissolved in an alcohol solution, and the alcohol solution includes 20 to 80 wt% water and 20 to 80 wt% alcohol solvent; the alcohol solution with this concentration ratio has a strong impact on the ⁇ -cyclodextrin derivatives.
  • Dextrin derivatives have better dissolving and dispersing effects, and also facilitate the subsequent crystallization and precipitation of lumbrokinase cyclodextrin inclusion complex from the solution system.
  • the ⁇ -cyclodextrin derivative is dissolved into an alcohol solution with an ethanol mass percentage of 20wt%, 40wt%, 60wt% or 80wt%.
  • the ⁇ -cyclodextrin derivative is selected from the group consisting of alkylated cyclodextrin derivatives, acyl cyclodextrin derivatives, N-functional cyclodextrin derivatives, and halogenated cyclodextrin derivatives. , 6-deoxycyclodextrin derivatives, sulfur-containing cyclodextrin derivatives, silyl cyclodextrin derivatives, blocked cyclodextrin derivatives, carboxyl-containing cyclodextrin derivatives, carbonate esters and At least one of carbamate glucosyl-cyclodextrin derivatives and cyclodextrin derivatives with modified monosaccharide units.
  • ⁇ -Cyclodextrin is a compound with a “cone” shape, “hydrophobic on the inside and hydrophilic on the outside” formed by 7 D-glucopyranose units connected end to end. This special cavity and the internal hydrophobic environment are conducive to the formation of inclusion complexes with lumbrokinase.
  • Natural ⁇ -CD has certain limitations in practical applications, such as poor water solubility, lack of effective functional points for enzymes, fixed cavity size and can only interact with molecules of a specific size, and luminescent groups without conjugation are spectrally inert. Therefore, chemical methods are used to modify it.
  • the alcoholic hydroxyl group is modified by alkylation, acylation, introduction of N-containing functional groups, halogenation, etherification, oxidation, esterification and cross-linking. , can effectively improve the performance of ⁇ -cyclodextrin.
  • the modified ⁇ -cyclodextrin derivative forms an inclusion complex with lumbrokinase, which can better increase the stability of the drug, prevent oxidation and decomposition of the drug, improve the dissolution and bioavailability of the drug, reduce the toxic and side effects of the drug, and mask the side effects of the drug.
  • Drug odor and odor can be used to improve the stability of the drug, prevent oxidation and decomposition of the drug, improve the dissolution and bioavailability of the drug, reduce the toxic and side effects of the drug, and mask the side effects of the drug.
  • the ⁇ -cyclodextrin derivative is selected from dimethyl- ⁇ -cyclodextrin.
  • the ⁇ -cyclodextrin derivative has the advantages of good water solubility, low nephrotoxicity and low hemolysis, and is a A good excipient, it can not only form an inclusion complex with lumbrokinase with good structure and performance stability. Making lumbrokinase into an inclusion complex to mask the odor of lumbrokinase can protect the drug from destruction through physical shielding and metabolic shielding.
  • dimethyl- ⁇ -cyclodextrin can promote the absorption of the active ingredient of lumbrokinase drugs from the mucosa through the paracellular pathway.
  • the transdermal absorption enhancer is selected from the group consisting of lecithin, sodium deoxycholate, sodium chenodeoxycholate, and lauric acid nitrogen. At least one of ketone, sodium caprate, sodium lauryl sulfate, sodium salicylate, glycyrrhetinic acid, and sodium glycyrrhizate.
  • the transdermal absorption accelerator used in the embodiments of the present application can increase the amount and speed of absorption of the active ingredients in the lumbrokinase oral adhesive tablets through the mucosa, improve the absorption efficiency of the lumbrokinase oral adhesive tablets in the oral cavity, and make the active pharmaceutical ingredients pass through the oral cavity and cheeks. Absorbed directly into the bloodstream by mucous membranes.
  • the lubricant is selected from at least one of calcium stearate, sodium stearate, magnesium stearate, stearic acid, sodium stearyl fumarate, and zinc stearate.
  • lubricants such as calcium stearate are added during the preparation of lumbrokinase oral adhesive tablets, which is beneficial to preventing sticking during the tableting process.
  • the glidant is selected from at least one of micropowder silica gel, microcrystalline cellulose, and silica.
  • Glidants such as micropowder silica gel used in the embodiments of this application are used to improve the fluidity of the material to ensure uniform weight difference of the tablets and uniformity of lumbrokinase content.
  • the flavoring agent is selected from at least one of sucralose, aspartame, and acesulfame potassium.
  • 2 to 8 parts of lubricant, 2 to 8 parts of glidant, 2 to 8 parts of flavoring agent, 4 to 16 parts of transdermal absorption enhancer are packaged with lumbrokinase cyclodextrin.
  • the compounds are mixed.
  • the mixing step includes: mixing calcium stearate with micronized silica gel and sucralose, then mixing with lecithin, and then adding lumbrokinase inclusion complex in equal amounts. Mix well.
  • the mixture is mixed with 40 to 160 parts of diluent I, 40 to 160 parts of dry adhesive, 60 to 240 parts of cross-linked polymer, and 60 to 240 parts of diluent I.
  • Agent II is mixed and then tableted.
  • lubricants, glidants, flavoring agents, transdermal absorption enhancers and lumbrokinase cyclodextrin inclusion complexes of the same or similar quantities are first mixed in small quantities, and then mixed with other large quantities of materials. Mixing the auxiliary materials evenly can help avoid uneven mixing caused by large differences in the quantity of materials.
  • it is also conducive to improving the tableting performance of the material, and is conducive to the attachment of lumbrokinase oral adhesive tablets in the oral mucosa, allowing direct administration into the bloodstream through the oral mucosa.
  • the step of tablet processing includes: mixing the mixture with diluent I, dry adhesive, cross-linked polymer, and diluent II, and then compressing the mixture into plain tablets to obtain lumbrokinase oral adhesive tablets.
  • the mixture is mixed with diluent I, dry adhesive, cross-linked polymer, and diluent II, and then directly pressed into a 0.5 g lumbrokinase oral adhesive tablet with a 12 mm flat punch.
  • the lumbrokinase oral adhesive tablets contain 300,000 to 500,000 units per tablet, and the active ingredient content is high.
  • the lumbrokinase oral adhesive tablets with this content have the ability to change blood rheology, microcirculation, platelets, activity, improving vascular endothelial cell function, anti-thrombosis and other activities, especially for the treatment of ischemic stroke.
  • the diluent I is selected from at least one of glucose binding agent, maltitol, maltodextrin, and dextran; it can promote the combination of each raw material component in the lumbrokinase oral adhesive tablet and improve the oral cavity of lumbrokinase. Stability of adhesive sheets.
  • diluent II is selected from at least one of lactose, pregelatinized starch, compressible sucrose, compressible starch, and mannitol.
  • the diluent II used in the embodiments of this application is easily soluble in water, odorless, slightly sweet, and stable in nature. It can improve the fluidity and compressibility of the material, make the surface smooth and clean, and is an auxiliary material for direct compression of powder. It can also directly compress lumbrokinase powder into tablets without heating and drying, ensuring that lumbrokinase is not inactivated by heating.
  • diluent II is lactose.
  • the cross-linked high molecular polymer is selected from at least one of carbomer, sodium carboxymethylcellulose, tragacanth, and sodium alginate.
  • the cross-linked polymers such as carbomer used in the embodiments of the present application are used for direct tableting, which allows the adhesive tablet to stick to the buccal mucosa after being moistened by oral fluid, thereby facilitating the stabilization of the lumbrokinase inclusion complex through the buccal mucosa. absorb.
  • the dry binder is selected from at least one of hypromellose, povidone, crospovidone, and low-substituted hypromellose.
  • Dry adhesives such as hypromellose used in the embodiments of this application can also be used as diluent II for lumbrokinase oral adhesive tablets, which is conducive to the stable combination of each raw material component during the tableting process and the preparation of stable structure and performance. Lumbrokinase oral adhesive tablets.
  • the second aspect of the embodiment of the present application provides a lumbrokinase oral adhesive tablet.
  • the lumbrokinase oral adhesive tablet includes raw material components: 8 to 32 parts of lumbrokinase, 40 to 160 parts of diluent I, 60 to 240 parts of diluent II, cross-linked high 60 to 240 parts of molecular polymer, 40 to 160 parts of dry adhesive, 0.6 to 4 parts of ⁇ -cyclodextrin derivative, 4 to 16 parts of transdermal absorption accelerator, 2 to 8 parts of glidant, and 2 to lubricant 8 parts and 2 to 8 parts of flavoring agent.
  • the lumbrokinase oral adhesive tablet provided in the second aspect of the embodiment of the present application includes 8 to 32 parts of raw material component lumbrokinase, 40 to 160 parts of diluent I, 60 to 240 parts of diluent II, and 60 to 240 parts of cross-linked polymer.
  • ⁇ -cyclodextrin derivatives can form inclusion complexes with lumbrokinase to prevent lumbrokinase from being affected by light, oxygen, heat and certain environmental factors, which is beneficial to enhancing drug stability, improving drug efficacy and preservation Extending the period can also increase the solubility and dissolution rate of the drug.
  • the lumbrokinase oral adhesive tablets can stably adhere to the mucosal surface in the oral cavity.
  • the administration route of lumbrokinase oral adhesive tablets is mucosal transdermal administration through transdermal absorption enhancers and other components.
  • the disintegration and dissolution time of enteric-coated tablets or capsules is omitted, and the It is quickly absorbed into the bloodstream directly from the oral mucosa, quickly enters the cerebral blood vessels, and quickly relieves the ischemic state of the cerebral blood vessels. It is especially suitable for the rescue treatment of acute stroke.
  • the lumbrokinase active ingredient in the lumbrokinase oral adhesive tablets in the embodiments of the present application has the activity of changing blood rheology, microcirculation, platelet activity, improving vascular endothelial cell function, anti-thrombosis and other activities.
  • the lumbrokinase active ingredient and fibrin have With special affinity, it not only hydrolyzes fibrin rich in plasminogen, but also hydrolyzes fibrin without plasminogen to dissolve thrombus; in addition, it can also directly hydrolyze fibrinogen to avoid its further formation into fibrin and thereby avoid the formation of fibrin. new thrombi; and can indirectly activate plasminogen to form plasmin.
  • the active ingredient of lumbrokinase has an anticoagulant effect by stimulating the release of tissue plasminogen activator (t-PA) from vascular endothelial cells, thereby enhancing the activity of t-PA, promoting the hydrolysis of coagulation factor I, and inhibiting platelet aggregation.
  • t-PA tissue plasminogen activator
  • the lumbrokinase oral adhesive tablet includes: 8 to 32 parts of lumbrokinase, 40 to 160 parts of glucose binding agent, 60 to 240 parts of lactose, 60 to 240 parts of carbomer, and 40 to 40 parts of hypromellose. 160 parts, 0.6 to 4 parts of dimethyl- ⁇ -cyclodextrin, 4 to 16 parts of lecithin, 2 to 8 parts of micronized silica gel, 2 to 8 parts of calcium stearate and 2 to 8 parts of sucralose.
  • the lumbrokinase oral adhesive tablets formulated in the embodiments of the present application have antipyretic, sedative, anticonvulsant, thrombolytic, anticoagulant, reduced platelet aggregation, reduced blood viscosity effects on the nerve, blood, and circulatory systems, and can reduce blood viscosity.
  • reduce platelet aggregation improve microcirculation, have good thrombolytic and anticoagulant effects in vivo and in vitro, and have few adverse reactions.
  • it can be quickly absorbed into the bloodstream directly from the oral mucosa, quickly enter the cerebral blood vessels, and quickly relieve the ischemic state of the cerebral blood vessels. It is especially suitable for the rescue treatment of acute stroke.
  • the content of lumbrokinase in the lumbrokinase oral adhesive tablet is 300,000 to 500,000 units per tablet.
  • the third aspect of the embodiment of the present application provides an application of a lumbrokinase oral adhesive sheet.
  • the lumbrokinase oral adhesive sheet prepared by the above method, or the above-mentioned lumbrokinase oral adhesive sheet, is applied to the oral mucosa of the patient.
  • the application of the lumbrokinase oral adhesive tablet provided in the third aspect of the embodiment of the present application can be directly applied to the patient's oral mucosa, and is directly absorbed into the bloodstream by the oral mucosa, quickly enters the cerebral blood vessels, and provides rapid relief.
  • the ischemic state of cerebral blood vessels omits the disintegration and dissolution time of enteric-coated tablets or capsules, and is especially suitable for the rescue treatment of acute stroke.
  • lumbrokinase oral adhesive tablets can be used in therapeutic drugs for ischemic stroke.
  • a lumbrokinase oral adhesive tablet, its raw material formula is shown in Table 1 below, and its preparation includes the steps:
  • a lumbrokinase oral adhesive tablet has a raw material formula as shown in Table 1 below, and its preparation method is the same as Example 1.
  • Example 1 Example 2 lumbrokinase 20 20 Glucose binder 80 80 lactose 100 100 carbomer 150 150 150 hypromellose 100 100 dimethyl- ⁇ -cyclodextrin 3 3 Lecithin 6 10 Micropowder silica gel 10 5 Calcium stearate 5 5 Sucralose 5 5
  • Example 1 In order to verify the progress of the embodiments of the present application, the following performance tests were conducted on the lumbrokinase oral adhesive tablets prepared in Example 1 and Example 2:
  • the test method is: use a self-made device to measure adhesion, as shown in Figure 2.
  • one side of the upper plastic sheet is fixed on an iron stand, and the other side is used to fix the biofilm material; one side of the lower plastic sheet is used Attach the adhesive piece to the other side and connect the thin plastic bag.
  • Egg shell membrane was selected as the biofilm material.
  • the lumbrokinase oral adhesive tablets prepared in Examples 1 and 2 of the present application have high adhesion to biofilm materials through in vitro adhesion force, indicating that the lumbrokinase oral adhesive tablets prepared in Examples of the present application have high adhesion to biofilm materials.
  • the adhesive tablet can stably adhere to the inner wall of the oral cavity, which facilitates the rapid absorption of the lumbrokinase oral adhesive tablet into the bloodstream through the oral mucosa, quickly enters the cerebral blood vessels, and quickly relieves the ischemic state of the cerebral blood vessels.
  • test method is:
  • test solution The lumbrokinase oral adhesive tablets prepared in Examples 1 and 2 were tested according to the paddle method specified in the "Pharmacopoeia of the People's Republic of China" (2020 Edition Four General Chapters 0931).
  • the temperature is (37 ⁇ 0.5)°C
  • the dissolution medium is 100mL artificial saliva
  • the rotation speed is 100r/min
  • 1mL is sampled regularly at 0.5, 1, 2, 4, 6, 8, and 10h, and the cumulative release is calculated using the regression equation.
  • test method is:

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Abstract

L'invention concerne un comprimé adhésif buccal de lumbrokinase, son procédé de préparation et son utilisation. Le procédé de préparation du comprimé adhésif buccal de lumbrokinase comprend les étapes suivantes : dissolution de 0,6 à 4 parts d'un dérivé de β-cyclodextrine dans un solvant, et ajout de 8 à 32 parts de lumbrokinase pour préparer un complexe d'inclusion lumbrokinase-cyclodextrine ; mélange de 2 à 8 parts d'un lubrifiant, 2 à 8 parts d'un agent glissant, 2 à 8 parts d'un agent aromatique et 4 à 16 parts d'un activateur d'absorption transdermique avec le complexe d'inclusion lumbrokinase-cyclodextrine, puis avec 40 à 160 parts d'un diluant I, 40 à 160 parts d'un adhésif sec, 60 à 240 parts d'un haut polymère réticulé et 60 à 240 parts d'un diluant II, puis façonnage en comprimé pour obtenir le comprimé adhésif buccal de lumbrokinase. Le comprimé adhésif buccal de lumbrokinase est administré par voie transdermique à travers les muqueuses. Le comprimé est directement absorbé dans le sang à travers les muqueuses et entre rapidement dans les vaisseaux cérébraux pour soulager rapidement l'état ischémique des vaisseaux cérébraux. Le comprimé est particulièrement adapté au traitement de secours de l'apoplexie cérébrale aiguë.
PCT/CN2022/108675 2022-05-09 2022-07-28 Comprimé adhésif buccal de lumbrokinase, son procédé de préparation et son utilisation WO2023216429A1 (fr)

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CN1814284A (zh) * 2005-12-12 2006-08-09 北京大学 提高蚓激酶口服吸收生物利用度的方法
WO2010029453A1 (fr) * 2008-09-10 2010-03-18 Pt.Dexa Medica Composition d'agent thrombolytique et anti-thrombotique ainsi que son procédé de production
CN103386122A (zh) * 2013-07-12 2013-11-13 长春远大国奥制药有限公司 一种蚓激酶肠溶片及其制备方法
CN105497068A (zh) * 2015-12-25 2016-04-20 张超 人工牛黄甲硝唑口腔贴片及其制备方法
CN106214716A (zh) * 2016-08-31 2016-12-14 中国热带农业科学院热带作物品种资源研究所 一种含有艾纳香提取物的口腔片剂及其制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102451162A (zh) * 2010-10-21 2012-05-16 重庆市力扬医药开发有限公司 经口腔粘膜吸收的奥氮平药物
CN102106836A (zh) * 2010-12-21 2011-06-29 青岛黄海制药有限责任公司 一种含有阿莫曲普坦的口腔粘附片剂及其制备方法和应用
CN103156816A (zh) * 2011-12-19 2013-06-19 重庆市力扬医药开发有限公司 经口腔粘膜吸收的阿莫曲坦药物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1814284A (zh) * 2005-12-12 2006-08-09 北京大学 提高蚓激酶口服吸收生物利用度的方法
WO2010029453A1 (fr) * 2008-09-10 2010-03-18 Pt.Dexa Medica Composition d'agent thrombolytique et anti-thrombotique ainsi que son procédé de production
CN103386122A (zh) * 2013-07-12 2013-11-13 长春远大国奥制药有限公司 一种蚓激酶肠溶片及其制备方法
CN105497068A (zh) * 2015-12-25 2016-04-20 张超 人工牛黄甲硝唑口腔贴片及其制备方法
CN106214716A (zh) * 2016-08-31 2016-12-14 中国热带农业科学院热带作物品种资源研究所 一种含有艾纳香提取物的口腔片剂及其制备方法

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