WO2023216429A1

WO2023216429A1 - Lumbrukinase buccal adhesive tablet, preparation method therefor and use thereof

Info

Publication number: WO2023216429A1
Application number: PCT/CN2022/108675
Authority: WO
Inventors: 管悦琴; 孙盛华; 王秀兰
Original assignee: 广西纯正堂制药有限公司
Priority date: 2022-05-09
Filing date: 2022-07-28
Publication date: 2023-11-16
Also published as: CN115006356B; CN115006356A

Abstract

Disclosed are a lumbrukinase buccal adhesive tablet, a preparation method therefor and use thereof. The preparation method for the lumbrukinase buccal adhesive tablet comprises the following steps: dissolving 0.6-4 parts of a β-cyclodextrin derivative into a solvent, and adding 8-32 parts of lumbrokinase to prepare a lumbrokinase-cyclodextrin inclusion complex; mixing 2-8 parts of a lubricant, 2-8 parts of a glidant, 2-8 parts of a flavoring agent and 4-16 parts of a transdermal absorption enhancer with the lumbrokinase-cyclodextrin inclusion complex, and then with 40-160 parts of a diluent I, 40-160 parts of a dry adhesive, 60-240 parts of a cross-linked high polymer and 60-240 parts of a diluent II, and tableting to obtain the lumbrokinase buccal adhesive tablet. The lumbrokinase buccal adhesive tablet is transdermally administrated through mucous membranes. The tablet is directly absorbed into the blood through mucous membranes, and quickly enters cerebral vessels to quickly relieve the ischemic state of cerebral vessels. The tablet is particularly suitable for rescue treatment of acute cerebral apoplexy.

Description

Lumbrokinase oral adhesive tablets and preparation methods and applications thereof

This application claims priority to the Chinese patent application submitted with the China Patent Office on May 9, 2022, with the application number 202210499808.3 and the invention name "lumbrokinase oral adhesive tablets and preparation methods and applications thereof", and its entire content has been approved This reference is incorporated into this application.

Technical field

This application relates to the field of pharmaceutical technology, specifically to a lumbrokinase oral adhesive tablet and its preparation method and application.

Background technique

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. These treatments are not designed to solve the problems of cerebral blood circulation obstruction, infarction and neurological damage that occur after the onset of ischemic stroke. Therefore, these methods are called It is the general treatment method for ischemic stroke. Improving cerebral blood circulation and protecting neurological function are the specific treatments for ischemic stroke.

In the 1980s, 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. Patients cannot significantly reduce the risk of cardiovascular and cerebrovascular diseases, but studies of other drugs (including cilostazol and dipyridamole) show that aspirin still has room for improvement in preventing stroke reinfarction and prognosis; ② Aspirin's bleeding The risks cannot be ignored; ③Aspirin resistance. Therefore, the efficacy and safety of aspirin in preventing cardiovascular and cerebrovascular events are still controversial, which has prompted the pharmaceutical industry to re-examine the miracle drug "aspirin" and also provided an opportunity to use other treatments and drugs to treat ischemic stroke.

technical problem

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.

Technical solutions

In order to solve the above technical problems, the technical solutions adopted in the embodiments of this application are:

In a first aspect, a method for preparing lumbrokinase oral adhesive tablets is provided, which is characterized in that it includes the following preparation steps:

Dissolve 0.6 to 4 parts of β-cyclodextrin derivatives into the solvent, add 8 to 32 parts of lumbrokinase for inclusion treatment, and obtain a lumbrokinase cyclodextrin inclusion complex;

Mix 2 to 8 parts of lubricant, 2 to 8 parts of glidant, 2 to 8 parts of flavoring agent, and 4 to 16 parts of transdermal absorption enhancer with the lumbrokinase cyclodextrin inclusion compound Process to obtain a mixture;

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.

In a second aspect, a lumbrokinase oral adhesive tablet is provided, 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 β-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.

In a third aspect, 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 provided by the embodiments of the present application 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. On the one hand, 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. On the other hand, 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 provided by the embodiments of the present application 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. 40 to 160 parts of dry adhesive, 0.6 to 4 parts of β-cyclodextrin derivatives, 4 to 16 parts of transdermal absorption accelerator, 2 to 8 parts of glidant, 2 to 8 parts of lubricant and flavoring agent 2 to 8 parts; among them, β-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. By cross-linking the polymer, 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. Compared with traditional enteric-coated preparations, 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 provided by the embodiments of the present application 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.

Description of the drawings

In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings needed to be used in the description of the embodiments or exemplary technologies will be briefly introduced below. Obviously, the drawings in the following description are only for the purpose of the present application. For some embodiments, for those of ordinary skill in the art, other drawings can be obtained based on these drawings without exerting creative efforts.

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.

Embodiments of the invention

In order to make the purpose, technical solutions and advantages of the present application clearer, the present application will be described in detail below in conjunction with the drawings and embodiments. It should be understood that the specific embodiments described here are only used to explain the present application and are not used to limit the present application.

In this application, the term "and/or" describes the relationship between related objects, indicating that there can be three relationships. For example, 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.

In this application, "at least one" refers to one or more, and "plurality" 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). For example, "at least one of a, b, or c", or "at least one of a, b, and 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.

It should be understood that in various embodiments of the present application, 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.

The terminology used in the embodiments of the present application is only for the purpose of describing specific embodiments and is not intended to limit the present application. As used in the embodiments and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise.

The 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. Specifically, the mass in the description of the embodiments of this application may be mass units well known in the chemical industry such as μg, mg, g, kg, etc.

The terms "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. For example, without departing from the scope of the embodiments of the present application, the first XX may also be called the second XX, and similarly, the 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.

As shown in Figure 1, 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:

S10. Dissolve 0.6 to 4 parts of β-cyclodextrin derivatives into the solvent, add 8 to 32 parts of lumbrokinase for inclusion treatment, and obtain a lumbrokinase cyclodextrin inclusion complex;

S20. Mix 2 to 8 parts of lubricant, 2 to 8 parts of glidant, 2 to 8 parts of flavoring agent, and 4 to 16 parts of transdermal absorption enhancer, and then include it with lumbrokinase cyclodextrin The materials are mixed to obtain a mixture;

S30. Mix the mixture 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 perform tableting processing. , to obtain lumbrokinase oral adhesive tablets.

The preparation method of lumbrokinase oral adhesive tablets provided in the first aspect of the embodiment of the present application includes dissolving the β-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. On the one hand, 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. On the other hand, 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.

In some embodiments, in the above step S10, 0.6 to 4 parts of β-cyclodextrin derivatives are dissolved into a solvent to prepare a β-cyclodextrin derivative solution, and then 8 to 32 parts of lumbrokinase are added. Inclusion processing. The β-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. Specifically, since the molecular structure of cyclodextrin is composed of more than 6 glucoses connected through α-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. At the same time, 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 β-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. In some embodiments, the mass ratio of β-cyclodextrin derivatives to lumbrokinase is 1: (6.5-26.5); the β-cyclodextrin derivatives in this ratio have better inclusion rates and lumbrokinase. Inclusion stability. In some specific embodiments, the mass ratio of β-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.

In some embodiments, the step of inclusion treatment includes: dissolving the β-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. In some specific embodiments, 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. In some specific embodiments, the β-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. In some embodiments, 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.

In some embodiments, the β-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 β-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. In some specific embodiments, the β-cyclodextrin derivative is dissolved into an alcohol solution with an ethanol mass percentage of 20wt%, 40wt%, 60wt% or 80wt%.

In some embodiments, the β-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. β-Cyclodextrin (β-CD) 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 β-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. Without changing the cyclic skeleton, 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 β-cyclodextrin. The modified β-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.

In some embodiments, the β-cyclodextrin derivative is selected from dimethyl-β-cyclodextrin. The β-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. Moreover, dimethyl-β-cyclodextrin can promote the absorption of the active ingredient of lumbrokinase drugs from the mucosa through the paracellular pathway.

In some embodiments, in the above step S20, 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.

In some embodiments, the lubricant is selected from at least one of calcium stearate, sodium stearate, magnesium stearate, stearic acid, sodium stearyl fumarate, and zinc stearate. In the embodiment of the present application, 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.

In some embodiments, 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.

In some embodiments, the flavoring agent is selected from at least one of sucralose, aspartame, and acesulfame potassium. Use flavoring agents such as sucralose to improve or shield the bitter taste, irritation, etc. of drugs to improve patient compliance.

In some embodiments, 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. In some specific embodiments, 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. By first mixing a small amount of calcium stearate, micronized silica gel and sucralose in the same or similar quantities, then adding lecithin and mixing, then adding lumbrokinase inclusion complex and mixing evenly, it is beneficial to improve the uniformity of the mixture. Avoid uneven mixing.

In some embodiments, in the above step S30, 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. In the embodiment of the present application, 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. In addition, 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.

In some embodiments, 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. In some specific embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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. In some specific embodiments, diluent II is lactose.

In some embodiments, 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.

In some embodiments, 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 β-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. , 40 to 160 parts of dry adhesive, 0.6 to 4 parts of β-cyclodextrin derivatives, 4 to 16 parts of transdermal absorption accelerator, 2 to 8 parts of glidant, 2 to 8 parts of lubricant and 2 flavoring agents ~8 parts; among them, β-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. By cross-linking the polymer, 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. Compared with traditional enteric-coated preparations, 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. Specifically: 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. In addition, 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. At the same time, by inhibiting the increase in platelet cytoplasm [Ca ²⁺ ] and the phosphorylation of JNK-1, it inhibits the increase in the expression level of platelet Ps, thus exerting an anti-platelet activation effect.

In some specific embodiments, 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-β-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. And 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.

In some embodiments, 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. Compared with the original enteric-coated preparations, 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.

In some embodiments, lumbrokinase oral adhesive tablets can be used in therapeutic drugs for ischemic stroke.

In order to make the above implementation details and operations of the present application clearly understood by those skilled in the art, and to significantly reflect the advanced performance of the lumbrokinase oral adhesive tablets and their preparation methods in the embodiments of the present application, the above are illustrated below through multiple embodiments. Technical solutions.

Example 1

A lumbrokinase oral adhesive tablet, its raw material formula is shown in Table 1 below, and its preparation includes the steps:

1. Add the prescribed amount of dimethyl-β-cyclodextrin to the 80wt% ethanol solution at 40°C, stir to dissolve, and prepare a saturated solution. Weigh the prescribed amount of lumbrokinase and place it in dimethyl-β-cyclodextrin water or ethanol solution, mix it with a high-speed tissue masher at 12000r/min for 120 minutes, refrigerate at 4°C until crystallization precipitates, filter it, and make it anhydrous. After washing with ethanol and vacuum drying, the lumbrokinase β-cyclodextrin inclusion complex is obtained.

2. Mix calcium stearate with micronized silica gel and sucralose, then mix with lecithin, add lumbrokinase inclusion complex, mix in equal amounts, and then mix with glucose binding agent, hypromellose , lactose, carbomer, and lactose are mixed evenly, and directly pressed with a 12mm flat punch into plain tablets of 0.5g each. Each tablet contains 300,000 units of lumbrokinase.

Example 2

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.

Table 1

原料组分Raw material components	实施例1Example 1	实施例2Example 2
蚓激酶lumbrokinase	2020	2020
葡萄糖结合剂Glucose binder	8080	8080
乳糖lactose	100100	100100
卡波姆carbomer	150150	150150
羟丙甲纤维素hypromellose	100100	100100
二甲基-β-环糊精dimethyl-β-cyclodextrin	33	33
卵磷脂Lecithin	66	1010
微粉硅胶Micropowder silica gel	1010	55
硬脂酸钙Calcium stearate	55	55
三氯蔗糖Sucralose	55	55

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:

1. Determination of adhesion in vitro. The test method is: use a self-made device to measure adhesion, as shown in Figure 2. In the figure, 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. After soaking in artificial saliva for 45 minutes, cut a small square of 2cm × 2cm and stick it to the upper plastic sheet with strong double-sided tape. Take 6 pieces of the lumbrokinase oral adhesive tablets prepared in Examples 1 and 2 to be tested, and fix the other side of one piece at a time on the plastic sheet below with strong double-sided tape. After moistening it with artificial saliva, quickly stick it to the egg. film, while continuously applying an external force of 10g for 5 minutes, and then slowly dripping purified water into the plastic bag with a 10mL graduated pipette, recording the volume of water used when the adhesive sheet falls off, and the adhesion force is the sum of the masses of water, plastic plate and plastic bag. (g) indicates.

The test results are shown in Table 2 below:

Table 2

It can be seen from the test results in Table 1 above that 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.

2. In vitro release measurement, the test method is:

① Preparation of standard solution: Take lumbrokinase standard and add 0.9% sodium chloride solution to make solutions with concentrations of 10000, 8000, 6000, 4000 and 2000 units in 1 mL.

② Prepare standard curve: Mix 39 mL of heated agarose solution, 39 mL of fibrinogen solution and 3 mL of thrombin, pour into a 14cm diameter petri dish, leave at room temperature for 1 hour, and punch a hole for sample injection. Add 10 μL of sample to each well and place at a constant temperature of 37°C for 18 hours. Measure the area of the molten circle. Taking the logarithm of the unit number of lumbrokinase standard as the abscissa and the logarithm of the product of the two vertical diameters of the soluble ring of the lumbrokinase standard as the ordinate, calculate the standard curve regression equation, Y=0.7933X+3.8944, R ² =0.9955.

③ Preparation of 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)℃, the dissolution medium is 100mL artificial saliva, the rotation speed is 100r/min, and 1mL is sampled regularly at 0.5, 1, 2, 4, 6, 8, and 10h, and the cumulative release is calculated using the regression equation.

④Measurement method: Substitute the logarithm of the product of the two vertical diameters of the dissolved circle of the test product into the regression equation Y = 0.7933X + 3.8944 (R ² = 0.9955), and calculate the number of potency units of the test product.

The test results are shown in Table 3 below:

table 3

3. Determination of the in vitro swelling rate of the adhesive sheet. The test method is:

Take 42 adhesive tablets of each prescription (divided into 7 groups, 6 tablets in each group), put them into the rotating basket of the dissolution apparatus, and weigh each initial mass. Then, place the rotating basket into a dissolution cup containing 0.9L of artificial saliva, maintain a constant temperature (37±0.1)°C in a water bath, and rotate at 100r/min. Take out each set of adhesive sheets at 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, and 8.0 hours after starting the experiment. Use filter paper to absorb the water around the basket and weigh it. The swelling of each adhesive sheet at different times is calculated through the mass change. percentage. Perform linear regression with swelling percentage (Ep) versus time (t), Y=11.075X+2.2238, R ² =0.9996.

The test results are shown in Table 4 below:

Table 4

It can be seen from the test results in Tables 3 and 4 above that the lumbrokinase oral adhesive tablets prepared in Examples 1 and 2 of the present application have better in vitro release and in vitro swelling rates. Compared with enteric-coated preparations, enteric-coated tablets or tablets are omitted. The disintegration and dissolution time of the capsule allows it to be quickly absorbed directly into the bloodstream 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 above are only optional embodiments of the present application and are not used to limit the present application. Various modifications and variations may be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of this application shall be included in the scope of the claims of this application.

Claims

A method for preparing lumbrokinase oral adhesive tablets, which is characterized by including the following preparation steps:

Dissolve 0.6 to 4 parts of β-cyclodextrin derivatives into the solvent, add 8 to 32 parts of lumbrokinase for inclusion treatment, and obtain a lumbrokinase cyclodextrin inclusion complex;

Mix 2 to 8 parts of lubricant, 2 to 8 parts of glidant, 2 to 8 parts of flavoring agent, and 4 to 16 parts of transdermal absorption enhancer with the lumbrokinase cyclodextrin inclusion compound Process to obtain a mixture;

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.
The preparation method of lumbrokinase oral adhesive tablets according to claim 1, wherein the step of inclusion treatment includes: dissolving the β-cyclodextrin derivative into an alcohol solution, adding the lumbrokinase , after inclusion for 60 to 120 minutes at a temperature of 20 to 80°C and a rotation speed of 8000 to 12000 r/min, refrigerate until crystallization precipitates, and the lumbrokinase cyclodextrin inclusion complex is isolated.
The preparation method of lumbrokinase oral adhesive tablets according to claim 2, wherein the β-cyclodextrin derivative is selected from the group consisting of alkylated cyclodextrin derivatives, acyl-containing cyclodextrin derivatives, N-functional cyclodextrin derivatives, halogenated cyclodextrin derivatives, 6-deoxycyclodextrin derivatives, sulfur-containing cyclodextrin derivatives, silyl cyclodextrin derivatives, blocked cyclodextrin At least one of a fine derivative, a carboxyl-containing cyclodextrin derivative, a carbonate and carbamate glucose-cyclodextrin derivative, and a cyclodextrin derivative that changes a monosaccharide unit.
The method for preparing lumbrokinase oral adhesive tablets according to claim 3, wherein the mass ratio of the β-cyclodextrin derivative to the lumbrokinase is 1: (6.5-26.5).
The method for preparing lumbrokinase oral adhesive tablets according to claim 3, wherein the alcohol solution includes 20 to 80 wt% of water and 20 to 80 wt% of alcohol solvent.
The method for preparing lumbrokinase oral adhesive tablets according to claim 3, wherein the β-cyclodextrin derivative is selected from dimethyl-β-cyclodextrin.
The preparation method of lumbrokinase oral adhesive tablets according to any one of claims 4 to 6, wherein the diluent I is selected from at least one of glucose binding agents, maltitol, maltodextrin and dextran. kind.
The preparation method of lumbrokinase oral adhesive tablets according to any one of claims 4 to 6, wherein the diluent II is selected from the group consisting of pregelatinized starch, lactose, compressible sucrose, compressible starch, and manna. At least one kind of alcohol.
The preparation method of lumbrokinase oral adhesive tablet according to any one of claims 4 to 6, wherein the transdermal absorption enhancer is selected from the group consisting of lecithin, sodium deoxycholate, sodium chenodeoxycholate, lauric acid nitrogen
At least one of ketone, sodium caprate, sodium lauryl sulfate, sodium salicylate, glycyrrhetinic acid, and sodium glycyrrhizate.
The preparation method of lumbrokinase oral adhesive tablets according to any one of claims 4 to 6, wherein the cross-linked polymer is selected from the group consisting of carbomer, sodium carboxymethylcellulose, and tragacanth. , at least one of sodium alginate.
The preparation method of lumbrokinase oral adhesive tablets according to any one of claims 4 to 6, wherein the dry adhesive is selected from the group consisting of hypromellose, povidone, cross-linked povidone, low-substituted At least one kind of hydroxypropylcellulose.
The preparation method of lumbrokinase oral adhesive tablets according to any one of claims 4 to 6, wherein the lubricant is selected from the group consisting of calcium stearate, sodium stearate, magnesium stearate, stearic acid, At least one of sodium stearyl fumarate and zinc stearate.
The method for preparing lumbrokinase oral adhesive tablets according to any one of claims 4 to 6, wherein the glidant is selected from at least one selected from the group consisting of micropowder silica gel, microcrystalline cellulose, and silicon dioxide.
The method for preparing lumbrokinase oral adhesive tablets according to any one of claims 4 to 6, wherein the flavoring agent is selected from at least one selected from the group consisting of sucralose, aspartame, and acesulfame potassium.
The preparation method of lumbrokinase oral adhesive tablets according to claim 1, wherein the step of tableting processing includes: mixing the mixture with the diluent I, the dry adhesive, the cross-linking agent After mixing the high molecular polymer and the diluent II, the tablets are pressed into plain tablets to obtain the oral adhesive tablets of lumbrokinase.
The preparation method of lumbrokinase oral adhesive tablets according to claim 15, wherein the content of lumbrokinase in the lumbrokinase oral adhesive tablets is 300,000 to 500,000 units per tablet.
A lumbrokinase oral adhesive tablet, 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, 60 to 240 parts of diluent II, cross-linked polymer polymer 60 to 240 parts of material, 40 to 160 parts of dry adhesive, 0.6 to 4 parts of β-cyclodextrin derivatives, 4 to 16 parts of transdermal absorption accelerator, 2 to 8 parts of glidant, and 2 to 8 parts of lubricant and 2 to 8 parts of flavoring agents.
The lumbrokinase oral adhesive tablet according to claim 17, characterized in that 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, and carbomer 60 to 240 parts, hypromellose 40 to 160 parts, dimethyl-β-cyclodextrin 0.6 to 4 parts, lecithin 4 to 16 parts, micronized silica gel 2 to 8 parts, calcium stearate 2 to 8 parts 2 to 8 parts of sucralose.
An application of lumbrokinase oral adhesive tablet, characterized in that the lumbrokinase oral adhesive tablet prepared by the method of any one of claims 1 to 16, or the lumbrokinase oral adhesive tablet of any one of claims 17 to 18 The oral adhesive sheet is applied to the patient's oral mucosa.