Sublingual film agent for allergic shock

Abstract

The invention provides a sublingual film agent for allergic shock, which is mainly prepared from the following raw materials in percentage by mass: 10-80% of an active ingredient, 10-80% of an auxiliary agent and the balance of a solvent, 10%-75% of a polymer film-forming material; 0.1%-20% of a surfactant; 2.5%-30% of saccharides; 1.5%-20% of a thickening agent; 0.1%-10% of a biological adhesive material; 0.1%-10% of a penetration enhancer; wherein the polymer film-forming material comprises pullulan and other polymer film-forming materials; the mass ratio of the pullulan to the other polymer film-forming materials is (3: 1)-(1: 3); the mass ratio of the polymer film-forming material to the thickening agent is (10: 1)-(1: 1). The film agent is convenient for administration, good in compliance, accurate in dosage and stable in quality; a new adrenaline administration choice is provided for patients, the price is lower, and the maintenance cost is avoided.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, in particular to a sublingual film for anaphylactic shock. Background Art

[0002] Anaphylactic shock, also known as severe allergic reaction or systemic allergic reaction, is a medical emergency that can progress rapidly and endanger life. The World Allergy Organization (WAO) Severe Allergic Reaction Guidelines (2020) mentions that the global incidence of severe allergic reactions is 50-112 per 100,000 people per year, and the incidence rate is increasing year by year. Allergies are full of unknowns and uncertainties. Severe allergies that can occur at any time and anywhere put patients under heavy pressure. Self-help for patients outside the hospital is very important.

[0003] Epinephrine is the first-line treatment for anaphylactic shock and the first choice for this indication. Currently, there is only one injection formulation available on the market at home and abroad. The World Allergy Organization (WAO) "Guidelines for Severe Allergic Reactions 2020", China's "Clinical Practice Guidelines for Emergency Management of Severe Allergic Reactions (2020)", the American Academy of Allergy and Asthma and Immunology (AAAAI), the European Academy of Allergy and Clinical Immunology (EAACI) and other guidelines all recommend that patients with a history of severe allergic reactions need to stock up on epinephrine auto-injection pens for self-treatment, especially when they are in situations where medical assistance may be delayed, such as in remote locations or travel difficulties.

[0004] However, the automatic injectors currently on the market have few options for dosage and needle length, and face challenges such as insufficient training of administration personnel leading to injection injuries, patients with needle phobia, and high costs. There is an urgent need to develop new dosage forms that are easy to use and carry and have low costs.

[0005] Epinephrine has a significant first-pass effect after oral administration. Part of it is directly taken up by adrenergic nerve endings in the blood, and the remaining absorbed part is quickly inactivated by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) in the intestinal mucosa and liver, converted into ineffective metabolites, and cannot reach effective blood concentrations.

[0006] The sublingual mucosa is thin and rich in blood vessels, so drugs are absorbed quickly and can take effect quickly, which is suitable for acute attacks. At the same time, drug absorption through the sublingual mucosa can avoid first-pass metabolism or degradation in the gastrointestinal tract and liver, thereby improving bioavailability.

[0007] Therefore, researchers have carried out many attempts to administer epinephrine sublingually. For example, compositions comprising epinephrine and prodrugs thereof (CN118141792A), a sublingual spray of epinephrine for anaphylactic shock and its preparation method and application (CN113750046B), compositions of epinephrine and prodrugs with enhanced delivery (CN111465391A), Sublingual epinephrine formulations and methods of use (US20230225994A1), Sublingual epinephrine compositions including ph-modifying excipients and penetration enhancers and methods for use thereof (US20220000806A1), Sublingual epinephrine tablets (US20220133654A1), Pharmaceutical formulation for sublingual or buccal delivery of epinephrine or a prodrug thereof (US11021437B2), etc.

[0008] Currently, there is an urgent need for a new dosage form for anaphylactic shock that is easy to use and has good compliance.

[0009] In view of this, the present invention is proposed. Summary of the invention

[0010] The first purpose of the present invention is to provide a sublingual film for anaphylactic shock, which is easy to use and has good compliance; the drug is dispersed and adsorbed on the surface of the polymer material, and the aggregation between drug molecules is further reduced through the microbubble structure, the solubility of adrenaline is increased, and then the dissolution of the drug is enhanced, and the mucosal permeability of adrenaline is enhanced together with the permeation enhancer; at the same time, the microbubble sublingual film dissolves rapidly, which is conducive to the rapid absorption and effectiveness of the drug to achieve the purpose of first aid.

[0011] The second purpose of the present invention is to provide a method for preparing the above-mentioned sublingual film for anaphylactic shock. The preparation method is simple and forms uniform and stable microbubbles by controlling the stirring speed. A carbon dioxide atmosphere is maintained during the preparation process to reduce the contact between the drug and oxygen, thereby improving the stability of the drug. At the same time, high-speed stirring is performed in an ice water bath to increase the viscosity of the polymer film-forming material, which is beneficial to the stability of the microbubble structure, and low temperature can further improve the stability of the drug.

[0012] The third object of the present invention is to provide a sublingual film for anaphylactic shock containing a 1 μm-100 μm microbubble structure prepared by the above preparation method.

[0013] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are particularly adopted:

[0014] The present invention provides a sublingual film for anaphylactic shock, which is mainly prepared from the following raw materials in terms of mass percentage:

[0015]

[0016] In the present invention, the active ingredient is adrenaline, and the adrenaline is selected from one or more of adrenaline base, adrenaline tartrate or other effective adrenaline salts and adrenaline prodrugs.

[0017] Wherein, the polymer film-forming material includes pullulan and other polymer film-forming materials;

[0018] The mass ratio of the pullulan to other polymer film-forming materials is (3:1)-(1:3);

[0019] The mass ratio of the polymer film-forming material to the thickener is (10:1)-(1:1);

[0020] Preferably, the mass ratio of the polymer film-forming material to the thickener is 4:1.

[0021] In the present invention, sugars are selected as non-specific stabilizers, which can form a protective film on the surface of drug particles to prevent direct contact between particles, thereby inhibiting the crystallization process of the drug. At the same time, sugars help maintain the pH value of the dispersion system and prevent the instability of drug particles caused by pH changes. These two effects together improve the dispersion stability of the drug. At the same time, the content is limited. Too high or too low sugar content will lead to uneven drug dispersion, thereby affecting the stability of the sublingual film.

[0022] In the present invention, the polymer film-forming material includes pullulan and other polymer film-forming materials, and other polymer film-forming materials are conventional water-soluble polymer materials that can be used for film-forming in the art, specifically hydroxypropyl methylcellulose (HPMC), hydroxypropyl ethylcellulose (HPEC), polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), polyvinyl pyrrolidone (PVP), polyvinyl alcohol-polyethylene glycol graft copolymer, maltodextrin, polyethylene oxide (PEO) and hydroxypropyl starch. One or more. Pullulan and other commonly used water-soluble polymer film-forming materials are usually not completely miscible, and their mixed aqueous solution forms a two-phase system with a miscible interface between the two phases. And the interaction between different phases is weak, the stability of the miscible interface is usually low, and it is easily affected by external disturbances, such as mechanical vibration, shear force, etc., which leads to changes in the phase surface and rearrangement of the material molecules, resulting in a large number of bubbles. The present invention also limits the ratio between pullulan and other polymer film-forming materials. The mass ratio of pullulan to other polymer film-forming materials is (3:1)-(1:3). Within this ratio range, pullulan can form a two-phase miscible interface with the water-soluble polymer material, and has good foaming performance. When the pullulan content is excessive, the physical properties of the film-forming agent will be reduced, and when the pullulan content is too low, the two cannot form a two-phase miscible interface, resulting in poor foaming performance.

[0023] In the present invention, the surfactant is one or more of sodium dodecyl sulfate, Tween, poloxamer, lecithin and fatty acid glyceride. The surfactant can present a lower surface tension at the gas-liquid interface. Adding the surfactant to the mixed slurry can form a thin film at the gas-liquid interface, which is further conducive to the generation of richer and more delicate foam; at the same time, under the percentage selected by the present invention, the surfactant can be better mixed with other components, so that the generated microbubbles are more uniform and stable.

[0024] In the present invention, the thickener is one or more of a low molecular thickener and a macromolecular suspending agent / thickener; the low molecular thickener may be one or more of mannitol, xylitol, maltitol, erythritol, sorbitol, lactitol, cetyl alcohol and stearic acid; the macromolecular suspending agent / thickener may be one or more of gum arabic, agar, carrageenan, dextrin, gellan gum, guar gum, pectin, propylene glycol alginate, sodium carboxymethyl cellulose, starch, gelatin, tragacanth gum and gum. During the preparation process, the thickener can absorb a large amount of water in the reaction system, increase the viscosity of the slurry, improve the mechanical strength of the foam film, hinder the shrinkage of the foam and the penetration of the liquid, thereby improving the stability of the foam.

[0025] In the present invention, the selected bioadhesive material is one or more of chitosan, sodium alginate, carbomer, polycarbophil, xanthan gum and hyaluronic acid. The bioadhesive material forms a stable bond with the sublingual mucosa through the comprehensive effects of hydrogen bonds, covalent bonds, classical attraction and hydrophobic bonds, so that the film can be closely combined with the mucosa, so that the drug is fully released and maintained for a long time.

[0026] Preferably, as a further specific embodiment, the penetration enhancer is 2%-5%.

[0027] In the present invention, the ratio of the penetration enhancer is further limited, preferably 0.1%-10%. When the ratio of the penetration enhancer is low, the effect of promoting mucosal absorption is weak, and the drug effective concentration cannot be reached quickly; but when the dosage is too much, it will cause damage to the mucosa. More preferably, it is 2%-5%. Under this ratio range, it can better promote mucosal absorption, make the drug take effect quickly, and avoid damage to the mucosa.

[0028] Preferably, as a further specific embodiment, the mass ratio of the pullulan to other polymer film-forming materials is (2:1)-(1:2);

[0029] Preferably, the mass ratio of the polymer film-forming material to the thickener is (5:1)-(1.2:1);

[0030] Preferably, the mass ratio of the polymer film-forming material to the thickener is 4:1.

[0031] In the present invention, the ratio of the polymer film-forming material to the thickener is also limited. The mass ratio of the polymer film-forming material to the thickener is (10:1)-(1:1), and the more preferred mass ratio is (5:1)-(1.2:1), and the further preferred mass ratio is 4:1. The reason for limiting the ratio is that when the proportion of the thickener is too large, the thickener will make the mortar too viscous and difficult to stir, and the film formation is not conducive to the reduction of the proportion of the film-forming material; and when the proportion of the thickener is reduced, the proportion of the corresponding film-forming material is increased, which will make the mortar viscosity smaller and the foam stability time shorter, thereby affecting the size and uniformity of the microbubbles in the film production process.

[0032] Preferably, as a further specific embodiment, the sugar is one or more of sucrose, maltose, fructose, glucose, lactose, and trehalose;

[0033] Preferably, the sugar is sucrose.

[0034] In film dosage forms, sugars usually act as flavoring agents or thickeners, but in the present invention, sugars act as stabilizers to stabilize the drug, and sucrose is a disaccharide consisting of one molecule of glucose and one molecule of fructose, and has a better stabilizing effect than other monosaccharides or polysaccharides.

[0035] Preferably, as a further specific embodiment, the penetration enhancer is one or more of propylene glycol, polyoxyethylene ether, polyamide-amine (PAMAM), glyceryl monooleate, clove oil, angelica oil, peppermint oil, oleic acid, lauric acid, oleate, levulinic acid, oleyl oleate, and glyceryl trioleate;

[0036] Preferably, the penetration enhancer is a mixture of glyceryl monooleate and levulinic acid;

[0037] Preferably, the penetration enhancer is a mixture of monoolein and levulinic acid in a mass ratio of 1:1.

[0038] In the present invention, the microbubble membrane structure can increase the solubility of the drug and enhance the dissolution of the drug. At the same time, the penetration enhancer can cooperate with the microbubble membrane to enhance the permeability of the drug, so that the drug can be quickly absorbed, thereby achieving the purpose of first aid. At the same time in the present invention, the type and ratio of the penetration enhancer are limited; when the mass ratio of the preferred monoolein and levulinic acid is 1:1, levulinic acid can form hydrogen bonds with the hydroxyl and amino groups in the molecular structure of adrenaline through the carboxyl group in the molecular structure, thereby playing a role in dispersing and solubilizing adrenaline, increasing the contact area between the drug and the mucosa, thereby promoting penetration and absorption; monoolein can interact with the sublingual mucosa through the hydrophobic and hydrophilic groups in the molecular structure, reduce the cell membrane surface tension, thereby improving the mucosal permeability of the drug, and promoting drug diffusion and absorption; when the content of a certain component is too high or too low, it is easy to cause the permeability and absorption performance of the prepared film to be reduced.

[0039] In the present invention, other functional excipients can be selected for adjustment according to actual needs, preferably one or more of disintegrants, plasticizers, stabilizers, pH regulators, colorants and flavoring agents. Disintegrants are one or more of cross-linked polyvinylpyrrolidone (PVPP), sodium carboxymethyl cellulose and corn starch; plasticizers are one or more of glycerol, PEG, and triacetin; stabilizers can be one or more of cyclodextrin (including hydroxypropyl-β-cyclodextrin, hydroxybutyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin), BHT, BHA, sodium bisulfite, and sodium pyrosulfite; pH regulators are one or more of hydrochloric acid, citric acid and / or its salts, phosphoric acid and / or its salts, and carbonic acid and / or its salts; colorants are one or more of ferric oxide, lemon yellow, amaranth and brilliant blue; flavoring agents are one or more of sucralose, aspartame, stevia, mint flavor, strawberry flavor, and sweet orange flavor.

[0040] The present invention also provides a method for preparing a sublingual film for anaphylactic shock, comprising:

[0041] In an atmosphere of carbon dioxide, the other polymer film-forming materials are prepared into a water slurry, and pullulan is added to the water slurry, and stirred until dissolved in the first stage to obtain a mixed solution;

[0042] Subsequently, in an ice bath, active ingredients, surfactants, sugars, thickeners, bioadhesive materials and penetration enhancers are added to the mixed solution, and the mixture is stirred in the second stage until the slurry is in a fine and uniform micro-foam state, and then applied to obtain the mixture.

[0043] In the preparation method of the present invention, the carbon dioxide atmosphere can reduce the contact between the drug and oxygen; the ice bath can absorb the heat generated by the reaction system; and the stirring rate is controlled at the same time, thereby improving the stability of the drug.

[0044] Preferably, as a further specific embodiment, the mass concentration of the water slurry is 5wt%-40wt%;

[0045] Preferably, the mass concentration of the water slurry is 7wt%-30wt%.

[0046] During the preparation process, other polymer materials need to be prepared into a water slurry of a certain concentration and then mixed with pullulan. The reason is that when other polymer materials are used alone and mixed with pullulan, it is difficult to form a uniform and stable slurry; after adding a certain amount of water, especially keeping the mass concentration of the water slurry at 5wt%-40wt%, more preferably 7wt%-30wt%, the two can form a stable mixing system to ensure the uniformity and stability of the prepared film.

[0047] Preferably, as a further specific implementation, the stirring speed in the first stage is 600r / min-1000r / min, and the stirring speed in the second stage is 7000r / min-12000r / min;

[0048] Preferably, the stirring speed in the first stage is 800 r / min-1000 r / min, and the stirring speed in the second stage is 9000 r / min-12000 r / min.

[0049] Preferably, as a further specific implementation, the stirring time of the first stage is 4 min-10 min, and the stirring time of the second stage is 2 min-8 min;

[0050] Preferably, the stirring time of the first stage is 6 min-10 min, and the stirring time of the second stage is 4 min-6 min.

[0051] In the present invention, the stirring step is divided into two times, and the stirring time and stirring speed are limited. The stirring speed mainly affects the properties of the microbubbles. The first stage of stirring is low-speed stirring, and its purpose is to fully mix the materials. When the stirring rate and time are too low, the materials are not fully mixed, and the prepared film is difficult to be applied in practice; when the stirring rate is too high, it is easy to instantly generate many bubbles of different sizes, which is not conducive to the subsequent further shearing into uniform microbubbles. If the time is too long, heat will be generated, causing some materials to denature and affect the efficacy. The second stage of stirring is high-speed stirring, and the stirring rate and time are also controlled. When the stirring speed and time are both low, it is difficult to form microbubbles with small and uniform particle size; and when the speed is too high or the time is too long, heat is easily generated, affecting the stability of the active substance, and it is easy to cause the evaporation of water and change the performance of the slurry.

[0052] The present invention also provides a sublingual membrane for anaphylactic shock containing a 1 μm-100 μm microbubble structure prepared by the above preparation method.

[0053] Compared with the prior art, the present invention has the following beneficial effects:

[0054] (1) The sublingual film for anaphylactic shock prepared by the present invention is convenient to administer, has good compliance, accurate dosage and stable quality. It is also small in size, light in weight and easy to carry. It provides a new option for adrenaline administration for patients. At the same time, compared with injection pens, the sublingual film is cheaper and has no maintenance cost.

[0055] (2) The sublingual film for anaphylactic shock prepared by the present invention reduces the aggregation of drug molecules through the dispersion effect of polymer materials and the microbubble structure, thereby increasing the solubility of adrenaline, thereby increasing the dissolution of the drug, and synergistically enhances the mucosal permeability of adrenaline together with the permeation enhancer, which is beneficial to the rapid onset of the drug; at the same time, the rapid dissolution is beneficial to the rapid absorption and onset of the drug, and is suitable as an emergency medicine.

[0056] (3) The sublingual film for anaphylactic shock prepared by the present invention uses sugars as nonspecific stabilizers to inhibit the degradation and aggregation of adrenaline, making the drug more stable; at the same time, a carbon dioxide atmosphere is maintained during the preparation process to reduce the contact between the drug and oxygen, and high-speed stirring is performed in an ice water bath to increase the viscosity of the polymer film-forming material, which is beneficial to the stability of the microbubble structure and further improves the stability of the drug.

[0057] (4) The sublingual film for anaphylactic shock prepared by the present invention forms a loosely structured gel that remains in place while the sublingual film dissolves through the interaction between the bioadhesive material and the sublingual mucosa, thereby preventing the drug that cannot be absorbed by the sublingual mucosa in time from being lost with saliva when swallowed, thereby allowing the drug to be fully absorbed through the sublingual mucosa. DETAILED DESCRIPTION

[0058] The technical scheme of the present invention will be clearly and completely described below in conjunction with specific embodiments, but it will be appreciated by those skilled in the art that the following described embodiments are part of embodiments of the present invention, rather than all embodiments, and are only used to illustrate the present invention, and should not be considered as limiting the scope of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work, all belong to the scope of protection of the present invention. If specific conditions are not indicated in the embodiments, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer is not indicated in the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0059] Example 1

[0060] Epinephrine 10g;

[0061] Main film-forming material: pullulan 56.3 g;

[0062] Auxiliary film-forming material: hydroxypropyl methylcellulose 18.7g;

[0063] Surfactant Tween 80 0.1 g;

[0064] Sugars: sucrose 2.5g;

[0065] Thickener gelatin 7.5g;

[0066] Bioadhesive material Carbomer 0.1 g;

[0067] Penetration enhancer glyceryl monooleate 0.1 g;

[0068] Other excipients 4.7g;

[0069] Under a carbon dioxide atmosphere, 18.7 g of auxiliary film-forming material hydroxypropyl methylcellulose was prepared into a water slurry with a mass concentration of 5 wt%, and 56.3 g of main film-forming material pullulan was added to the water slurry, the stirring rod was turned on, and the speed was adjusted to 600 r / min and stirred at a low speed for 10 min to obtain a mixture;

[0070] Subsequently, in an ice water bath, 10 g of adrenaline, 800.1 g of surfactant Tween, 2.5 g of sugar sucrose, 7.5 g of thickener gelatin, 0.1 g of bioadhesive material carbomer, 0.1 g of penetration enhancer monoolein and 4.7 g of other auxiliary materials were added to the mixed solution in sequence, and the mixture was stirred at a high speed of 12000 r / min for 2 min to obtain a slurry, and the slurry was applied and dried.

[0071] Example 2

[0072] Dipifoline hydrochloride (adrenaline prodrug) 10g;

[0073] Main film-forming material: pullulan 2.5g;

[0074] Auxiliary film-forming material polyvinyl alcohol 7.5g;

[0075] Surfactant lecithin 20g;

[0076] Sugars: maltose 30g;

[0077] Thickener maltitol 10g;

[0078] Bioadhesive material sodium alginate 10 g;

[0079] Penetration enhancer levulinic acid 10g;

[0080] In a carbon dioxide atmosphere, 7.5 g of the auxiliary film-forming material polyvinyl alcohol was prepared into a water slurry with a mass concentration of 40 wt%, and 2.5 g of the main film-forming material pullulan was added to the water slurry, the stirring rod was turned on, and the speed was adjusted to 1000 r / min and stirred at a low speed for 4 minutes to obtain a mixture;

[0081] Subsequently, in an ice water bath, 10 g of dipivefrin hydrochloride, 20 g of surfactant lecithin, 30 g of maltose, 10 g of maltitol, 10 g of bioadhesive material sodium alginate and 10 g of permeation enhancer levulinic acid were added to the mixed solution in sequence, and the mixture was stirred at a high speed of 7000 r / min for 8 min to obtain a slurry, which was then applied and dried.

[0082] Example 3

[0083] Epinephrine hydrochloride 25g;

[0084] Main film-forming material: pullulan 16g;

[0085] Auxiliary film-forming material: hydroxypropyl cellulose 8g;

[0086] Surfactant fatty acid glyceride 5g;

[0087] Sugars: fructose 14g;

[0088] Thickener sorbitol 20g;

[0089] Bioadhesive material chitosan 5g;

[0090] Penetration enhancer lauric acid 5g;

[0091] Other auxiliary materials 2g;

[0092] Under a carbon dioxide atmosphere, 8 g of auxiliary film-forming material hydroxypropyl cellulose was prepared into a water slurry with a mass concentration of 7 wt%, and 16 g of main film-forming material pullulan was added to the water slurry, the stirring rod was turned on, and the speed was adjusted to 800 r / min and stirred at a low speed for 7 minutes to obtain a mixture;

[0093] Subsequently, in an ice water bath, 25 g of epinephrine hydrochloride, 5 g of surfactant fatty acid glyceride, 14 g of sugar fructose, 20 g of thickener sorbitol, 5 g of bioadhesive material chitosan, 5 g of penetration enhancer lauric acid and 2 g of other auxiliary materials were added to the mixed solution in sequence, and the mixture was stirred at a high speed of 9000 r / min for 6 min to obtain a slurry, and the slurry was applied and dried.

[0094] Example 4

[0095] Epinephrine 80g;

[0096] Main film-forming material: pullulan 3.5g;

[0097] Auxiliary film-forming material polyvinyl pyrrolidone 7g;

[0098] Surfactant poloxamer 1 g;

[0099] Sugars: glucose 3g;

[0100] Thickener cetyl alcohol 1.5g;

[0101] Bioadhesive material polycarbophil 2 g;

[0102] Penetration enhancer oleic acid 2g;

[0103] In a carbon dioxide atmosphere, 7 g of the auxiliary film-forming material polyvinyl pyrrolidone was prepared into a water slurry with a mass concentration of 30 wt%, and 3.5 g of the main film-forming material pullulan was added to the water slurry, the stirring rod was turned on, and the speed was adjusted to 900 r / min and stirred at a low speed for 6 minutes to obtain a mixture;

[0104] Then, in an ice water bath, add 80 g of adrenaline, 1 g of surfactant poloxamer, 3 g of sugar glucose, 1.5 g of thickener cetyl alcohol, 2 g of bioadhesive material polycarbophil and 2 g of penetration enhancer oleic acid to the mixed solution in sequence, and stir at a high speed of 10,000 r / min for 4 min to obtain a slurry, and apply and dry the slurry.

[0105] Example 5

[0106] Epinephrine tartrate 30g;

[0107] Main film-forming material: pullulan 20g;

[0108] Auxiliary film-forming material: hydroxypropyl methylcellulose 20g;

[0109] Surfactant sodium dodecyl sulfate 2g;

[0110] Sugars: fructose 7g;

[0111] Thickener dextrin 10g;

[0112] Bioadhesive material sodium alginate 3 g;

[0113] Penetration enhancer clove oil 4g;

[0114] Other auxiliary materials 4g;

[0115] Under a carbon dioxide atmosphere, 20 g of auxiliary film-forming material hydroxypropyl methylcellulose was prepared into a water slurry with a mass concentration of 25 wt%, and 20 g of main film-forming material pullulan was added to the water slurry, the stirring rod was turned on, and the speed was adjusted to 900 r / min and stirred at a low speed for 8 min to obtain a mixture;

[0116] Subsequently, in an ice water bath, 30 g of epinephrine tartrate, 2 g of surfactant sodium dodecyl sulfate, 7 g of sugar fructose, 10 g of thickener dextrin, 3 g of bioadhesive material sodium alginate, 4 g of penetration enhancer clove oil and 4 g of other auxiliary materials were added to the mixed solution in sequence, and the mixture was stirred at a high speed of 11000 r / min for 5 min to obtain a slurry, and the slurry was applied and dried.

[0117] Example 6

[0118] Epinephrine prodrug 52g;

[0119] Main film-forming material: pullulan 17.9g;

[0120] Auxiliary film-forming material: polyethylene oxide 7.1g;

[0121] Surfactant fatty acid glyceride 2g;

[0122] Sugars Lactose 5g;

[0123] Thickener agar 5g;

[0124] Bioadhesive material: hyaluronic acid 4 g;

[0125] Penetration enhancer oleyl oleate 7g;

[0126] In a carbon dioxide atmosphere, 7.1 g of polyethylene oxide, an auxiliary film-forming material, was prepared into a water slurry with a mass concentration of 35 wt%, and 17.9 g of pullulan, a main film-forming material, was added to the water slurry, a stirring rod was turned on, and the speed was adjusted to 700 r / min and stirred at a low speed for 5 min to obtain a mixture;

[0127] Subsequently, in an ice water bath, 52 g of adrenaline prodrug, 2 g of surfactant fatty acid glyceride, 5 g of carbohydrate lactose, 5 g of thickener agar, 4 g of bioadhesive material hyaluronic acid and 7 g of penetration enhancer oleyl oleate were added to the mixed solution in sequence, and the mixture was stirred at a high speed of 8000 r / min for 7 min to obtain a slurry, which was then applied and dried.

[0128] Example 7

[0129] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 5, except that the sugar is replaced by maltose, and the grams of the sugar itself remains unchanged.

[0130] Example 8

[0131] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 5, except that the sugar is replaced by glucose, and the gram weight of the sugar itself remains unchanged.

[0132] Example 9

[0133] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 5, except that the sugar is replaced by trehalose, and the gram weight of the sugar itself remains unchanged.

[0134] Example 10

[0135] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 5, except that the sugar is replaced by sucrose, and the gram weight of the sugar itself remains unchanged.

[0136] Embodiment 11

[0137] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 5, except that the sugars are replaced by sucrose and maltose, and the grams of the sugars themselves remain unchanged, including 3.5 g of sucrose and 3.5 g of maltose.

[0138] Example 12

[0139] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 5, except that the sugars are replaced by sucrose and glucose. The grams of the sugars themselves remain unchanged, including 3.5 g of sucrose and 3.5 g of glucose.

[0140] Embodiment 13

[0141] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 10, except that the permeation enhancer is replaced by oleic acid, and the gram weight of the permeation enhancer itself remains unchanged.

[0142] Embodiment 14

[0143] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 10, except that the permeation enhancer is replaced by polyoxyethylene ether, and the gram weight of the permeation enhancer itself remains unchanged.

[0144] Embodiment 15

[0145] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 10, except that the permeation enhancer is replaced by propylene glycol and oleyl oleate, and the grams of the permeation enhancer itself remains unchanged, including 2 g of propylene glycol and 2 g of oleyl oleate.

[0146] Example 16

[0147] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 10, except that the permeation enhancer is replaced by monoolein and levulinic acid, and the mass ratio of monoolein to levulinic acid is 2:1. The weight of the permeation enhancer itself remains unchanged, with 2.7 g of monoolein and 1.3 g of levulinic acid.

[0148] Embodiment 17

[0149] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 10, except that the permeation enhancer is replaced by glyceryl monooleate and levulinic acid, and the mass ratio of glyceryl monooleate to levulinic acid is 1:1, and the gram weight of the permeation enhancer itself remains unchanged, wherein glyceryl monooleate is 2g and levulinic acid is 2g.

[0150] Embodiment 18

[0151] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 10, except that the permeation enhancer is replaced by monoolein and levulinic acid, and the mass ratio of monoolein to levulinic acid is 1:2. The weight of the permeation enhancer itself remains unchanged, with 1.3 g of monoolein and 2.7 g of levulinic acid.

[0152] Embodiment 19

[0153] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 17, except that the auxiliary film-forming material is prepared into a water slurry with a mass concentration of 2 wt%.

[0154] Embodiment 20

[0155] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 17, except that the auxiliary film-forming material is prepared into a water slurry with a mass concentration of 50 wt%.

[0156] Embodiment 21

[0157] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 17, except that the stirring speed is adjusted to 1500 r / min after the main film-forming material pullulan and the auxiliary film-forming material are added.

[0158] Embodiment 22

[0159] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 17, except that the stirring speed is adjusted to 200 r / min after the main film-forming material pullulan and the auxiliary film-forming material are added.

[0160] Embodiment 23

[0161] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 17, except that the stirring speed is adjusted to 700 r / min after adding the active ingredient, surfactant, sugar, thickener, bioadhesive material and permeation enhancer.

[0162] Embodiment 24

[0163] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 17, except that the stirring speed is adjusted to 18,000 r / min after the active ingredient, surfactant, sugar, thickener, bioadhesive material and permeation enhancer are added.

[0164] Comparative Example 1

[0165] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 17, except that the mass ratio between the main film-forming material and the auxiliary film-forming material is changed to 4:1, and the total grams of the two remain unchanged, including 32g of pullulan and 8g of hydroxypropyl methylcellulose.

[0166] Comparative Example 2

[0167] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 17, except that the mass ratio between the main film-forming material and the auxiliary film-forming material is changed to 1:4, and the total grams of the two remain unchanged, including 8 g of pullulan and 32 g of hydroxypropyl methylcellulose.

[0168] Comparative Example 3

[0169] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 17, except that pullulan, the main film-forming material, is not used.

[0170] Comparative Example 4

[0171] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 17, except that no auxiliary film-forming material is used.

[0172] Comparative Example 5

[0173] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 17, except that no sugar is used.

[0174] Comparative Example 6

[0175] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 17, except that no thickener is used.

[0176] Comparative Example 7

[0177] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 17, except that no bioadhesive material is used.

[0178] Comparative Example 8

[0179] The specific preparation steps of the adrenaline sublingual film are the same as those in Example 17, except that no penetration enhancer is used.

[0180] Comparative Example 9

[0181] The specific preparation steps of the adrenaline sublingual film are consistent with those in Example 17. The mass ratio of the polymer film-forming material to the thickener is 13:1, the polymer film-forming material is 46.4 g, and the thickener dextrin is 3.6 g.

[0182] Comparative Example 10

[0183] The specific preparation steps of the adrenaline sublingual film are consistent with those in Example 17. The mass ratio of the polymer film-forming material to the thickener is 1:13, the polymer film-forming material is 3.6 g, and the thickener dextrin is 46.4 g.

[0184] Effect Example 1

[0185] The epinephrine sublingual films obtained in the examples and comparative examples were tested, and the test data are shown in Table 1. The dissolution time was measured according to the Chinese Pharmacopoeia disintegration time test method (General Rule 0921), and the solubility in a pH 6.8 medium was measured according to the Chinese Pharmacopoeia dissolution test method (General Rule 0931 Second Method).

[0186] Among them, Example 17 is the example with the best performance.

[0187] Table 1 Appearance and performance of sublingual film

[0188]

[0189]

[0190]

[0191] Based on the above data, we can draw the following conclusions:

[0192] It can be known from the experimental data in Table 1 that the effects of the adrenaline sublingual films prepared by the schemes of Examples 1-24 of the present invention are better than those of the adrenaline sublingual films prepared by Comparative Examples 1-10. Among them, the adrenaline sublingual film prepared according to the scheme of Example 17 is the most excellent in performance. Through the specific mass ratio between pullulan and auxiliary polymer materials, it has good foaming ability, and a large number of bubbles can be generated by stirring at low speed under a carbon dioxide atmosphere, and then active ingredients, surfactants, sugars, thickeners, bioadhesive materials and penetration enhancers are added, and a kind of adrenaline sublingual film with microbubbles of 1μm-100μm is obtained after high-speed stirring under ice-water bath conditions. The drug is dispersed and adsorbed on the surface of the polymer material, and the aggregation between drug molecules is further reduced by the microbubble structure, the solubility of adrenaline is increased, and then the dissolution of the drug is enhanced, and the penetration enhancer and the mucosal permeability of adrenaline are enhanced together. The microbubble sublingual film dissolves rapidly, which is conducive to the rapid absorption and effectiveness of the drug to achieve the purpose of emergency treatment. At the same time, the bioadhesive material in the prescription interacts with the sublingual mucosa, so that the sublingual film is dissolved while partially forming a loosely structured gel to stay in place, avoiding the loss of drugs that cannot be absorbed by the sublingual mucosa in time with saliva swallowing, so that the drug is fully absorbed by the sublingual mucosa. And further adding sugars in the prescription as non-specific stabilizers can inhibit the degradation and aggregation of the drug, thereby improving the stability of the drug. The main film-forming material and auxiliary film-forming material and their ratio selected by the present invention have a certain influence on the effect of the adrenaline sublingual film finally prepared. The present invention has been found through long-term creative labor that only by mixing the main film-forming material pullulan and the auxiliary film-forming material, and when the pullulan and the auxiliary film-forming material are in an appropriate mass ratio, the two are evenly mixed and stirred at a low speed to produce good foaming properties, so that a uniform and large amount of microbubbles can appear in the subsequent high-speed stirring. Therefore, it can be known from the experimental data of Examples 1-24 that the prepared film can produce uniform microbubbles only when the mass ratio of pullulan to the auxiliary film-forming material is (3:1)-(1:3). This is because when the pullulan ratio is too high, the film-forming physical properties are poor, and when the pullulan ratio is too low, it is not easy to form a two-phase miscible interface and a large number of bubbles cannot be generated.

[0193] By comparing Example 17 and Examples 19-20, it can be known that the mass concentration formed when preparing the auxiliary film-forming material water slurry in the present invention has a certain influence. From the experimental data of Example 17, it can be known that when the mass concentration of the auxiliary film-forming material water slurry is in an appropriate range, the bubble diameter of the microbubbles formed is significantly better than that of Examples 19-20. Because it is difficult to form a uniform and stable slurry when other polymer materials are mixed with pullulan alone; a certain amount of water needs to be added thereto to form a water slurry, and the mass concentration is maintained in the range of 5wt%-40wt%, more preferably 7wt%-30wt% to form a stable mixed system with pullulan, thereby ensuring the uniformity and stability of the prepared film.

[0194] By comparing Example 17 with Examples 21-24, it can be known that the stirring speed after adding the main film-forming material pullulan and the auxiliary film-forming material in the present invention has a certain influence. From the experimental data of Example 17, it can be known that when the stirring speed is in an appropriate range, the bubble diameter of the microbubbles formed is significantly better than that of Examples 21-24, because only when the pullulan and the auxiliary film-forming material are mixed and stirred at a low speed of 600-1000r / min, the two can produce a large number of uniform bubbles, and then after high-speed stirring of 7000-12000r / min, microbubbles can be formed. Therefore, the stirring speed is very important for the present invention. This is because when the stirring speed is too low, it is not conducive to the sufficient mixing between pullulan and the auxiliary film-forming material, affecting the subsequent stirring. If the stirring speed is too fast, many bubbles of different sizes will be generated at the moment of stirring, resulting in uneven microbubbles and affecting the film effect.

[0195] In summary, in the present invention, the diameter of the microbubbles has an effect on the appearance of the film and the physical properties of the prepared film, and the stirring time, number of times and the concentration of the prepared water slurry will affect the physical properties of the film, and the effect on the physical properties is specifically reflected in the dissolution time and dissolution. In terms of appearance, the scattering effect of the microbubbles on light makes it impossible for the naked eye to identify the bubbles, so that the film is uniformly opaque white. The smaller the bubble diameter, the more uniform the film looks; the bubble diameter is too large, and the naked eye can see obvious bubbles, the appearance of the film is unqualified, and it is not convenient to use. Therefore, the size of the microbubbles of the sublingual film prepared by the preparation method of the present invention is uniform and the diameter is less than 100 μm, the appearance of the film is qualified, and it is convenient to use. From the comparison of Examples 1-18 and 19-20, it can be seen that when the mass concentration of the water slurry is controlled at 5wt%-40wt%, the diameter of the prepared film can be made smaller, thereby significantly improving the dissolution of the film; when it exceeds this range, the diameter of the film will become larger, but the dissolution rate will be significantly reduced. From the comparison between Examples 1-18 and Examples 21-24, it can be seen that when the number of stirring times, time and speed are within the range defined by the present invention, the diameter of the prepared film can be less than 100 μm, and the dissolution time can be shortened and the solubility can be significantly improved; when it exceeds the range defined by the present invention, the final dissolution time will be significantly increased, and the solubility will be significantly reduced. It can be seen that changes in preparation conditions will affect the diameter of the microbubbles, thereby affecting the physical properties of the film.

[0196] And by comparing examples 1-18 and comparative example 6, it can be known that the use of thickener is extremely important for the present invention. It can be known from the experimental data of Examples 1-18 that when a thickener is added to the prescription and the mass ratio of the polymer film-forming material to the thickener is 4:1, the polymer film-forming material and the thickener can form a uniform grid structure, appropriately increase the viscosity of the polymer film-forming material, and facilitate film formation at the same time, and the grid structure can also make the generated microbubbles more stable, so that the prepared microbubble film has excellent dissolution performance and smaller bubble diameter. This is because after the microbubbles are generated, because the microbubbles themselves have certain instability, the present invention makes the microbubbles have better stability by adding a thickener.

[0197] By comparing Examples 1-18 and Comparative Example 7, it can be known that the use of bioadhesive materials is extremely important for the present invention. From the experimental data of Examples 1-18, it can be known that when bioadhesive materials are added to the prescription and the mass range is within 0.1%-10%, the obtained adrenaline sublingual film has excellent mucosal adhesion properties. This is because after the bioadhesive material is moistened and swelled, it comes into close contact with the sublingual mucosa through the comprehensive effects of mechanical intercalation, van der Waals forces, hydrogen bonds and hydrophobic bonds, so that the sublingual membrane partially forms a loosely structured gel while dissolving, and stagnates briefly in situ for a period of time. It can avoid that after the microbubble sublingual membrane dissolves rapidly, the released drug cannot be absorbed by the sublingual mucosa in time, and is lost with saliva swallowing, so that the drug can be fully absorbed through the sublingual mucosa.

[0198] By comparing Examples 1-18 and Comparative Example 8, it can be seen that the selection of the permeation enhancer is extremely important for the present invention. From the experimental data of Examples 16-18, it can be seen that when the selected permeation enhancer is a mixture of monoolein and levulinic acid, the permeation amount of the adrenaline sublingual film prepared therefrom within 0.5h is significantly better than that of other options.

[0199] By comparing Example 17 with Comparative Examples 9-10, it can be seen that the ratio between the polymer film-forming material and the thickener is very important in the present invention. It can be seen from the experimental data that when the proportion of the polymer film-forming material is large, the bubble diameter of the prepared film is large, which has a greater impact on the physical properties of the prepared product; at the same time, the proportion of the thickener is too low, resulting in a low viscosity of the slurry and a short foam stability time, which affects the size and uniformity of the microbubbles in the film production process. When the proportion of the polymer film-forming material is small, the corresponding proportion of the thickener is high, which will cause the slurry to be too viscous, which is not conducive to stirring, and the corresponding film-forming material is small, which is not conducive to film formation, resulting in unstable performance of the film prepared, and the technical effect required by the present invention cannot be achieved.

[0200] And by comparing examples 13-18, it can be known that the mass ratio between monoolein and levulinic acid is also very important for the present invention. From experimental data, it can be known that when the mass ratio between monoolein and levulinic acid of embodiment 17 is 1:1, the permeation amount of the prepared adrenaline sublingual film in 0.5h is higher than the mass ratio between monoolein and levulinic acid in embodiment 16 and embodiment 18, which is 2:1 and 1:2. This is because levulinic acid can form hydrogen bonds with the hydroxyl and amino groups in the molecular structure of adrenaline through the carboxyl group in the molecular structure, thereby playing a role in dispersing and solubilizing adrenaline, increasing the contact area between the drug and the mucosa, thereby promoting penetration and absorption. The molecular structure of monoolein has hydrophobic and hydrophilic groups at the same time, which can reduce the cell membrane surface tension to improve the mucosal permeability of the drug and promote drug diffusion absorption. If the levulinic acid ratio is too high and the monoolein ratio is too low, it is not conducive to reducing the surface tension of the cell membrane, and the permeability is insufficient. If the proportion of levulinic acid is too low and the proportion of monoolein is too high, it will be detrimental to the dispersion of the drug in the matrix, reduce the contact area between the drug and the mucosa, and lead to reduced drug absorption.

[0201] Effect Example 2

[0202] Take the adrenaline sublingual film obtained in Examples 7-12 and Comparative Example 5, remove the outer packaging, and conduct a high temperature test to examine the stability of the sample. The film was placed in a culture dish at 60°C for 10 days, and samples were taken on the 5th and 10th days to detect the related substances of adrenaline in the film, wherein the test data are shown in Table 2 below.

[0203] Table 2 Stability of sublingual film

[0204]

[0205] Based on the above data, we can draw the following conclusions:

[0206] By comparing Examples 7-12 and Comparative Example 5, it can be known that the presence of sugars is crucial to the stability of the finally prepared adrenaline sublingual film. It can be known from Example 10 that when the sugar is selected as sucrose, the prepared sublingual film is significantly better than other embodiments and comparative examples in terms of stability. This is because sugars are added as non-specific stabilizers during the preparation process of the adrenaline sublingual film of the present invention, which can form a protective film on the surface of the drug particles to prevent direct contact between particles, thereby inhibiting the crystallization process of the drug. At the same time, sugars help maintain the pH value of the dispersed system and prevent the instability of the drug particles caused by pH changes. These two effects jointly improve the dispersion stability of the drug, so that the impurity content of the prepared adrenaline sublingual film is still low after high temperature inspection.

[0207] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A sublingual film for anaphylactic shock, characterized in that: In terms of mass percentage, it is mainly made from the following raw materials: Active ingredient 10%-80%; Polymer film-forming materials 10%-75%; Wherein, the polymer film-forming material includes pullulan and other polymer film-forming materials; The mass ratio of the pullulan to other polymer film-forming materials is (3:1)-(1:3); The mass ratio of the polymer film-forming material to the thickener is (10:1)-(1:1).

2. The sublingual film for anaphylactic shock according to claim 1, characterized in that The penetration enhancer is 2%-5%.

3. The sublingual film for anaphylactic shock according to claim 1, characterized in that The mass ratio of the pullulan to other polymer film-forming materials is (2:1)-(1:2); Preferably, the mass ratio of the polymer film-forming material to the thickener is (5:1)-(1.2:1); Preferably, the mass ratio of the polymer film-forming material to the thickener is 4:

1.

4. The sublingual film for anaphylactic shock according to claim 1, characterized in that The sugar is one or more of sucrose, maltose, fructose, glucose, lactose and trehalose; Preferably, the sugar is sucrose.

5. The sublingual film for anaphylactic shock according to claim 1, characterized in that The penetration enhancer is one or more of propylene glycol, polyoxyethylene ether, polyamide-amine (PAMAM), glyceryl monooleate, clove oil, angelica oil, peppermint oil, oleic acid, lauric acid, oleate, levulinic acid, oleyl oleate, and glyceryl trioleate; Preferably, the penetration enhancer is a mixture of glyceryl monooleate and levulinic acid; Preferably, the penetration enhancer is a mixture of monoolein and levulinic acid in a mass ratio of 1:

1.

6. A method for preparing a sublingual film for anaphylactic shock according to any one of claims 1 to 5, characterized in that: The steps include: In an atmosphere of carbon dioxide, the other polymer film-forming materials are prepared into a water slurry, and pullulan is added to the water slurry, and stirred until dissolved in the first stage to obtain a mixed solution; Subsequently, in an ice bath, active ingredients, surfactants, sugars, thickeners, bioadhesive materials and penetration enhancers are added to the mixed solution, and the mixture is stirred in the second stage until the slurry is in a fine and uniform micro-foam state, and then applied to obtain the mixture.

7. The method for preparing the sublingual film for anaphylactic shock according to claim 6, characterized in that: The mass concentration of the water slurry is 5wt%-40wt%; Preferably, the mass concentration of the water slurry is 7wt%-30wt%.

8. The method for preparing the sublingual film for anaphylactic shock according to claim 6, characterized in that: The stirring speed of the first stage is 600r / min-1000r / min, and the stirring speed of the second stage is 7000r / min-12000r / min; Preferably, the stirring speed in the first stage is 800 r / min-1000 r / min, and the stirring speed in the second stage is 9000 r / min-12000 r / min.

9. The method for preparing the sublingual film for anaphylactic shock according to claim 6, characterized in that: The stirring time of the first stage is 4min-10min, and the stirring time of the second stage is 2min-8min; Preferably, the stirring time of the first stage is 6 min-10 min, and the stirring time of the second stage is 4 min-6 min.

10. A sublingual film for anaphylactic shock containing a 1 μm-100 μm microbubble structure prepared by the preparation method according to claim 6.

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