Pharmaceutical composition and application thereof

Abstract

The invention relates to the technical field of medicines, and provides a pharmaceutical composition and application thereof. The pharmaceutical composition is prepared from erdosteine, benpipralin phosphate, olopatadine hydrochloride and procaterol hydrochloride. The pharmaceutical composition has the effects of relieving cough, eliminating phlegm and relieving asthma at the same time. Meanwhile, the erdosteine, the benpipralin phosphate, the olopatadine hydrochloride and the procaterol hydrochloride are compounded to achieve a synergistic effect, and the olopatadine hydrochloride is compounded to inhibit inflammatory exudation caused by respiratory tract infection and relax respiratory tract smooth muscles, so that the cough relieving and phlegm eliminating effects of the pharmaceutical composition are effectively improved; the cough relieving effect of the pharmaceutical composition is obviously better than that of benpipralin phosphate, and the phlegm eliminating effect of the pharmaceutical composition is obviously better than that of erdosteine.

Description

Technical Field

[0001] The present application belongs to the field of pharmaceutical technology, and in particular relates to a pharmaceutical composition and its application. Background Art

[0002] Acute and chronic bronchitis is a chronic nonspecific inflammation of the trachea, bronchial mucosa and surrounding tissues caused by infectious or non-infectious factors. Repeated attacks of inflammation can cause the submucosal smooth muscle bundles to rupture and atrophy. Further progression of the lesion can cause proliferation of fibrous tissue around the trachea, infiltration and swelling of tracheal smooth muscle, and stiffness, collapse and spasm of the lumen, resulting in airway obstruction. The main clinical manifestations are repeated coughing, expectoration or wheezing.

[0003] During the acute and chronic upper respiratory tract infection attack period, coughing and expectoration are obvious. As the disease progresses, fever, coughing up yellow sputum, green sputum and / or wheezing may occur. The sputum is thick and difficult to cough up, blocking the respiratory tract. Bacteria can easily grow and multiply in the airway, causing lung infection. Repeated attacks can develop into chronic obstructive pulmonary disease, causing respiratory failure and endangering life. Clinically, it has been found that airway mucus blockage and high mucus secretion in elderly patients are the main factors that have an adverse effect on prognosis, and are related to the mortality rate caused by lung infection and other causes. Therefore, effectively controlling tracheal smooth muscle spasm, fully improving cough symptoms, reducing sputum viscosity and making it easy to cough up are of great significance to controlling the further spread and deterioration of respiratory tract infections.

[0004] In the existing treatment plan, patients with acute and chronic bronchitis are given two different drugs, cough suppressants and expectorants, to relieve the symptoms of acute and chronic upper respiratory tract infections. Different drugs work separately, the dosage of the drugs is large, and the patient compliance is relatively low. Therefore, there is an urgent need to provide a drug with more efficient expectorant and cough suppressant effects with lower dosage. Summary of the invention

[0005] The purpose of the present application is to provide a pharmaceutical composition and its application, so as to solve the technical problem that the expectorant drug preparation and the antitussive drug preparation in the prior art act separately and the drug dosage is large.

[0006] In order to achieve the above application purpose, the technical solution adopted in this application is as follows:

[0007] In a first aspect, the present application provides a pharmaceutical composition, which comprises erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride.

[0008] The compounding of the four active ingredients of the pharmaceutical composition of the embodiment of the present application, namely, erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride, has a synergistic effect, so that the pharmaceutical composition not only has the effects of relieving cough and removing phlegm at the same time, but also effectively improves the effects of relieving cough and removing phlegm of the pharmaceutical composition, so that the relieving cough effect of the pharmaceutical composition is significantly stronger than that of benproperine phosphate, and the removing phlegm effect is significantly stronger than that of erdosteine. Therefore, the pharmaceutical composition of the embodiment of the present application effectively improves the relieving cough effect of benproperine phosphate and the removing phlegm effect of erdosteine ​​under the same total dosage of the drug, and effectively reduces the total dosage of the drug under the same relieving cough and removing phlegm effects.

[0009] In a second aspect, the embodiments of the present application provide the use of the above-mentioned pharmaceutical composition in the preparation of at least one of expectorant drugs, antitussive drugs, antiasthmatic drugs, and antihistamine drugs.

[0010] Since the above pharmaceutical composition has good antitussive and expectorant effects, the pharmaceutical composition has good application prospects in the preparation of antitussive and / or expectorant drugs. At the same time, the pharmaceutical composition also has antiasthmatic and antihistamine effects.

[0011] In a third aspect, the present invention provides a pharmaceutical preparation. The pharmaceutical preparation of the present invention comprises the pharmaceutical composition described above and pharmaceutically acceptable excipients.

[0012] Since the above-mentioned pharmaceutical composition has good expectorant and antitussive effects, the pharmaceutical preparation of the present application also has good expectorant and antitussive effects, and can be used to treat or relieve symptoms such as excessive sputum and cough.

[0013] In a fourth aspect, the present invention provides a method for preparing a pharmaceutical preparation. The method for preparing a pharmaceutical preparation in the present invention comprises the following steps:

[0014] The pharmaceutical composition and pharmaceutically acceptable excipients are prepared according to the preparation process of pharmaceutical preparations to obtain pharmaceutical preparations.

[0015] Since the above-mentioned pharmaceutical composition has good expectorant and antitussive effects, the pharmaceutical preparation prepared by the pharmaceutical composition preparation method of the present application embodiment has good antitussive and expectorant effects, and at the same time improves asthma symptoms caused by various reasons. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained like these drawings without paying any creative work.

[0017] Figure 1 A schematic diagram of the structure of the oral adhesive sheet provided in the embodiment of the present application;

[0018] Figure 2 A schematic diagram of an exploded oral adhesive sheet provided in an embodiment of the present application;

[0019] Figure 3 Another schematic diagram of the structure of the oral adhesive sheet provided in the embodiment of the present application;

[0020] Figure 4 Schematic diagram of the structure of the in vitro adhesion force measurement device. DETAILED DESCRIPTION

[0021] In order to make the technical problems, technical solutions and beneficial effects to be solved by the present application more clearly understood, the present application is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.

[0022] In this application, the term "and / or" describes the association relationship of associated objects, indicating that there may be three relationships. For example, A and / or B can mean: A exists alone, A and B exist at the same time, and B exists alone. A and B can be singular or plural. The character " / " generally indicates that the associated objects are in an "or" relationship.

[0023] In this application, "at least one" means one or more, and "plurality" means two or more. "At least one of the following" or similar expressions refers to any combination of these items, including any combination of single items or plural items. For example, "at least one of a, b, or c", or "at least one of a, b, and c" can all mean: a, b, c, a~b (i.e. a and b), a~c, b~c, or a~b~c, where a, b, c can be single or multiple, respectively.

[0024] It should be understood that in the various embodiments of the present application, the size of the serial numbers of the above-mentioned processes does not mean the order of execution, some or all of the steps can be executed in parallel or sequentially, and the execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0025] The terms used in the embodiments of the present application are only for the purpose of describing specific embodiments, and are not intended to limit the present application. The singular forms "a", "an" and "the" used in the embodiments of the present application and the appended claims are also intended to include plural forms, unless the context clearly indicates other meanings.

[0026] The weight of the relevant components mentioned in the embodiment description of the present application can not only refer to the specific content of each component, but also represent the proportional relationship between the weights of the components. Therefore, as long as the content of the relevant components is proportionally enlarged or reduced according to the embodiment description of the present application, it is within the scope disclosed in the embodiment description of the present application. Specifically, the mass in the embodiment description of the present application can be μg, mg, g, kg and other mass units known in the chemical industry.

[0027] The terms "first" and "second" are used only for descriptive purposes to distinguish objects such as substances from each other, and should not be understood as indicating or implying relative importance or implicitly indicating the number of indicated technical features. For example, without departing from the scope of the embodiments of the present application, the first XX may also be referred to as the second XX, and similarly, the second XX may also be referred to as the first XX. Thus, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features.

[0028] In order to solve the technical problem in the prior art that different expectorants and cough suppressants work separately and the dosage of the drugs is large, the present application proposes the following technical solution.

[0029] In a first aspect, the present application provides a pharmaceutical composition, which comprises erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride.

[0030] Among them, erdosteine ​​has definite antitussive, expectorant and antioxidant effects. It is effective and safe for cough and sputum in patients with acute and chronic bronchitis. It is especially suitable for patients with thick sputum and difficulty expectorating. Taking it can reduce acute attacks and protect lung function. When the body is stressed, the activated neutrophils in the lungs release more elastase, which damages the lung tissue. Erdosteine ​​has a protective antiprotease effect, which keeps the protease-antiprotease system balanced, thereby protecting the lung tissue. Erdosteine ​​can be converted into active metabolites with free thiol groups in the liver, which can improve sputum rheology, relieve cough, improve tracheal epithelial ciliary clearance and transport mucus, inhibit bacterial adhesion to airway mucosal cells, and thus prevent airway infection. At the same time, erdosteine ​​can also significantly increase the concentration of amoxicillin antibiotics in mucus, thereby increasing the activity of antibiotics in the airway, enhancing the antibacterial treatment effect, and thus helping to control infection.

[0031] Benproperine phosphate is a white powder with a slight odor and bitter taste. It is easily soluble in water, slightly soluble in ethanol, chloroform or benzene, and insoluble in acetone or ether. Its chemical name is 1-[2-(-benzylphenoxy)-1-methylethyl]-piperidine phosphate, and its molecular formula is C 21 H 27NO·H3PO4. Benproperine phosphate has both peripheral and central non-narcotic antitussive effects, and its antitussive effect is 2-4 times stronger than codeine. It can block the sensory nerve impulses from the pulmonary pleural stretch receptors, and has a spasmolytic effect on bronchial smooth muscle. It has a certain inhibitory effect on the cough center, does not inhibit breathing, and is not addictive. In animal experiments, it has a local anesthetic effect similar to lidocaine and has a slight anti-inflammatory activity.

[0032] Olopatadine hydrochloride is used to treat urticaria in adults, itching caused by various skin diseases, and allergic rhinitis in children. The prior art shows that inflammatory mediators such as leukotriene B4 (LTB4), platelet activating factor (PAF), thromboxane B2 (TXB2), and interleukin (IL)-2 play an important role in the generation of itching by acting on the C-type nerve fiber endings that transmit itch sensation directly or by releasing other mediators. The high inhibitory effect of olopatadine hydrochloride on inflammatory mediators can significantly reduce the inflammation of the trachea and bronchitis caused by respiratory tract infections, thereby indirectly improving the cough symptoms caused by tracheal and bronchial inflammation. Olopatadine has clear anti-inflammatory activity, inhibits the chemotaxis of neutrophils and eosinophils, and can widely and effectively inhibit multiple inflammatory factors such as LTB4, PAF, TXB2, granulocyte-macrophage colony stimulating factor (GM-CSF), IL-6, IL-8, IL-4, IL-31, and has no anti-5-hydroxytryptamine effect. Studies on the effects of H1 receptor antagonists on cytokines conducted by relevant researchers have confirmed that olopatadine almost completely inhibits inflammatory factors such as GM-CSF, IL-8 and IL-6 that are dependent on histamine concentration and time, and its inhibitory effect on IL-8 is about 80 times that of cetirizine. Studies by Tamura et al. have confirmed that compared with antihistamines such as loratadine, cetirizine, fexofenadine, and chlorpheniramine, olopatadine has anti-inflammatory mediators IL-4, IL-1β, IL-6, GM-CSF, and has a stronger inhibitory effect on IL-4 and IL-6. The most common adverse reaction of H1 receptor antagonists is drowsiness caused by central inhibition, followed by dry mouth caused by anticholinergic effects. Olopatadine is also mainly characterized by these two adverse reactions, which are only mild to moderate and can be relieved without drug treatment. No adverse cardiac reactions, such as QT interval prolongation and ventricular tachycardia, were found. Olopatadine has no effect on cytochrome P450 enzyme activity and serum protein binding rate, so the possibility of drug interaction is small. No serious adverse reactions were found in olopatadine, which is relatively safe. As a new type of antihistamine, olopatadine has the effects of potent non-competitive antagonism of histamine receptors, anti-inflammatory factors, anti-neurogenic itch transmitters, and continuous stabilization of mast cell membranes. It fights itch in four dimensions and is the optimal choice for anti-itch medication in dermatology. It is also effective in treating allergic inflammatory diseases. It is relatively safe and has broad application prospects.

[0033] Procaterol Hydrochloride is an adrenergic receptor agonist. It activates adenylate cyclase by stimulating adrenergic receptors on the membrane of bronchial smooth muscle cells, which in turn catalyzes the conversion of intracellular adenosine triphosphate (ATP) into cyclic adenosine monophosphate (CAMP). As the concentration of CAMP in respiratory smooth muscle cells increases, the ratio of cyclic guanosine monophosphate (CAMP / CGMP) increases, producing a bronchodilator effect. It can also increase the concentration of CAMP in mast cell membranes, stabilize mast cell membranes, and inhibit the release of allergic mediators such as histamine, 5-hydroxytryptamine, and slow-reacting substances, thereby alleviating bronchospasm and respiratory mucosal congestion caused by these mediators. It indirectly inhibits cough caused by bronchospasm. Procaterol Hydrochloride is a highly selective β2 receptor agonist with a strong bronchial antispasmodic effect. A small dose can produce a significant bronchodilator effect, and the effect lasts for a long time, which can last for 10-12 hours at a time. The side effects of the cardiovascular system are mild. In addition, this product has a strong anti-allergic effect, can stabilize mast cell membranes, inhibit the release of allergic substances such as histamine, and has a good effect on bronchial asthma induced by allergens. Tolerance is not obvious.

[0034] The drug combination of the embodiment of the present application is combined with four active ingredients of erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride, so that the drug composition not only has the effects of relieving cough and removing phlegm at the same time. At the same time, it is found through experiments that erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride also have a synergistic effect, which can effectively improve the antitussive and expectorant effects of the drug composition, so that the antitussive effect of the drug composition is better than the antitussive effect of benproperine phosphate when used alone, and the expectorant effect of the drug composition is significantly enhanced compared with the expectorant effect of erdosteine ​​when used alone.

[0035] In some embodiments, the mass ratio of erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride can be (240-360): (30-60): (4-6): (0.08-0.12), and can be optionally 300:50:5:0.1, 300:40:5:0.1.

[0036] That is, in terms of weight, the weight of erdosteine ​​in the pharmaceutical composition of the embodiment of the present application can be 240 to 360 parts, and can be any weight between 240 and 360 parts, including 240 parts and 360 parts.

[0037] The weight proportion of benproperine phosphate can be 30 to 60 parts, and can be any weight proportion between 30 and 60 parts, including 30 parts and 60 parts.

[0038] The weight proportion of olopatadine hydrochloride can be 4 to 6 parts, and can be any weight proportion between 4 and 6 parts, including 4 parts and 6 parts.

[0039] The weight portion of Procaterol hydrochloride can be 0.08 to 0.12 parts, and can be any weight portion between 0.08 and 0.12 parts including 0.08 and 0.12 parts.

[0040] Controlling the compounding ratio of erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride within the above range can further promote the synergistic effect between the four active ingredients of erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride, and further improve the antitussive and expectorant effects of the pharmaceutical composition of the embodiment of the present application.

[0041] In some embodiments, in the pharmaceutical composition of the present application, the daily dosage of benproperine phosphate can be 0.85714-1.7143 mg / kg, which can be any value between 0.85714-1.7143 mg / kg, including 0.85714 mg / kg and 1.7143 mg / kg. The daily dosage of benproperine phosphate in the pharmaceutical composition of the present application is controlled within this range, and combined with other active ingredients, the antitussive and expectorant effects of the pharmaceutical composition are further improved.

[0042] In some embodiments, the four active components in the pharmaceutical composition of the present application embodiment can be mixed or separated from each other. In addition, two or three of the four active ingredients can be mixed, and the remaining active ingredients can be set separately. In the exemplary embodiment, erdosteine ​​in the pharmaceutical composition can be set separately, and benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride can be mixed. There is no specific limitation, and those skilled in the art can choose according to actual needs.

[0043] In a second aspect, the embodiments of the present application provide the use of the above-mentioned pharmaceutical composition in the preparation of at least one of expectorant drugs, antitussive drugs, antiasthmatic drugs, and antihistamine drugs.

[0044] Since the above pharmaceutical composition has good antitussive and expectorant effects, the pharmaceutical composition has good application prospects in the preparation of antitussive and / or expectorant drugs. At the same time, the pharmaceutical composition also has antiasthmatic and antihistamine effects, so that the pharmaceutical composition can be used in antiasthmatic drugs and antihistamine drugs.

[0045] In some embodiments, the excessive sputum and cough may be caused by respiratory inflammation caused by respiratory infection. In an exemplary example, the excessive sputum and cough may be caused by a cold.

[0046] In a third aspect, the present invention provides a pharmaceutical preparation. The pharmaceutical preparation of the present invention comprises the pharmaceutical composition described above and pharmaceutically acceptable excipients.

[0047] Since the above-mentioned pharmaceutical composition has good expectorant and antitussive effects, the pharmaceutical preparation of the present application also has good expectorant and antitussive effects, and can be used to treat or relieve the symptoms of excessive sputum and cough.

[0048] In some embodiments, the pharmaceutically acceptable excipients may include at least one of a diluent, a solubilizing agent, a hygroscopic agent, an emulsifier, a surfactant, a binder, a glidant, a lubricant, a pH adjuster, a suspending agent, a propellant, a filler, and a disintegrant.

[0049] In some embodiments, the pharmaceutical preparation of the present application can be a solid preparation, a semi-solid preparation, or a liquid preparation, without specific limitation. In the exemplary embodiment, the dosage form of the pharmaceutical preparation of the present application can be selected from any one of tablets, capsules, granules, pills, emulsions, inhalation preparations, gels, powders, patches, solutions, and suspensions.

[0050] In some embodiments, the pharmaceutical preparation of the present application can be an oral adhesive tablet. By making the pharmaceutical preparation of the present application into an oral adhesive tablet, the active ingredients can be concentrated and quickly absorbed into the blood through the oral mucosa, quickly exerting antitussive, expectorant and antiasthmatic effects, and can avoid the destructive effects of gastrointestinal and oral digestive enzymes on the active ingredients of the drug, as well as the first-pass effect of the liver produced by the liver drug enzyme, prolonging the action time of the drug, and significantly improving the bioavailability of the drug. In addition, by administering the drug through the oral adhesive tablet, it can also be removed in time when necessary to avoid further continuation or expansion of the harm of the drug.

[0051] In some embodiments, when the pharmaceutical preparation of the present application is an oral adhesive tablet, Figure 1 and Figure 2As shown, the oral adhesive sheet 10 may include a substrate 11 and a protective layer 12. The substrate 11 contains the above-mentioned pharmaceutical composition, and the two side surfaces of the substrate 11 are respectively a first surface 111 and a second surface 112, and the protective layer 12 is attached to the surface of the substrate 11, that is, the first surface 111. When the oral adhesive sheet 10 is used, the second surface 112 of the substrate 11 can be attached to the oral mucosa, and the protective layer 12 can effectively reduce or prevent the release of the active pharmaceutical ingredient from the first surface 111 of the substrate 11, thereby promoting the release of the active pharmaceutical ingredient from the second surface 112, and further promoting the direct absorption of the active pharmaceutical ingredient from the oral mucosa, reducing the dissipation of the active pharmaceutical ingredient from the first surface 111 into the oral cavity, reducing the active pharmaceutical ingredient from entering the esophagus and gastrointestinal tract through the oral cavity, further reducing the damage of the active pharmaceutical ingredient to the active pharmaceutical ingredient by the gastrointestinal tract and oral digestive enzymes and the first-pass effect of the liver, and further improving the bioavailability of the oral adhesive sheet.

[0052] In a further embodiment, in the oral adhesive sheet 10, the structures of the first surface 111 and the second surface 112 of the substrate 11 may be different. Figure 3 As shown, one side surface of the substrate 11 is an arc-shaped or deep arc-shaped structure, that is, the first surface 111 is an arc-shaped or deep arc-shaped structure; the other side surface of the substrate 11 is a plane structure, that is, the second surface 112 is a plane structure. Correspondingly, the protective layer 12 can also be an arc-shaped or deep arc-shaped structure, so that the protective layer 12 is attached to the arc-shaped or deep arc-shaped first surface 111. Such a structure of the oral adhesive sheet 10 enables the oral adhesive sheet 10 to better fit the oral mucosa; at the same time, it also enables the part of the substrate 11 other than the second surface 112 for releasing the active ingredient to be more fully sealed by the protective layer 12, thereby effectively preventing the active drug from escaping from the second surface 112 to the oral cavity, further reducing the entry of the active drug ingredients into the esophagus and gastrointestinal tract through the oral cavity, reducing the damage of the gastrointestinal tract and oral digestive enzymes to the active drug ingredients and the first-pass effect of the liver, and further improving the bioavailability of the oral adhesive sheet.

[0053] In some embodiments, the substrate 11 may include the following components by weight:

[0054]

[0055] The oral adhesive sheet 10 of the embodiment of the present application improves the adhesion of the oral adhesive sheet 10 on the buccal mucosa by adding a mucosal adhesive agent to the base sheet 11, and increases the intercellular space of the buccal mucosa through the mucosal absorption promoter, the osmotic pressure promoter and the water-soluble diluent, thereby significantly increasing the permeability of the buccal mucosa cells, and at the same time increasing the osmotic pressure of the erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride solutions, promoting the rapid release of the active ingredients of the drugs, and passively diffusing through the oral mucosa, thereby increasing the release rate and absorption speed of the drugs, promoting the rapid onset of the drugs, and improving the bioavailability of the drugs.

[0056] In some embodiments, the weight proportion of erdosteine ​​may be 240 to 360 parts, and may be any weight proportion between 240 and 360 parts, including 240 and 360 parts.

[0057] In some embodiments, the weight proportion of benproperine phosphate may be 30 to 60 parts, and may be any weight proportion between 30 and 60 parts, including 30 parts and 60 parts.

[0058] In some embodiments, the weight proportion of olopatadine hydrochloride may be 4 to 6 parts, and may be any weight proportion between 4 and 6 parts, including 4 and 6 parts.

[0059] In some embodiments, the weight portion of Procaterol hydrochloride can be 0.08 to 0.12 parts, and can be any weight portion between 0.08 and 0.12 parts including 0.08 and 0.12 parts.

[0060] By controlling the weight fractions of erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride within the range, the synergistic effect between the four active ingredients of erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride is further promoted, and the antitussive and expectorant effects of the oral adhesive sheet 10 are improved. In addition, the excipients in the oral adhesive sheet 10 can be combined to further promote the release of different active pharmaceutical ingredients in the oral adhesive sheet 10 at a relatively stable ratio, thereby promoting the absorption of the active pharmaceutical ingredients at a relatively stable ratio, and further improving the efficacy of the oral adhesive sheet.

[0061] In some embodiments, the weight percentage of the mucosal absorption enhancer can be 64 to 96 parts, and can be any weight percentage between 64 and 96 parts, including 64 and 96 parts. Controlling the weight of the mucosal absorption enhancer within this range further promotes the absorption of the four active ingredients of erdosteine, benproperine phosphate, olopatadine hydrochloride, and procaterol hydrochloride.

[0062] In some embodiments, the mucosal absorption promoter may include at least one of poloxamer, glycofurol, lecithin, and isopropyl myristate. These mucosal absorption promoters can effectively accelerate the mucosal transdermal absorption of the active pharmaceutical ingredient in the oral adhesive sheet 10 of the present embodiment.

[0063] In some embodiments, the weight percentage of the mucosal adhesive can be 64 to 96 parts, and can be any weight percentage between 64 and 96 parts, including 64 parts and 96 parts. The weight percentage of the mucosal adhesive is controlled within this range to further improve the adhesion of the oral adhesive sheet, and at the same time, combined with other excipients such as mucosal absorption enhancers and osmotic pressure enhancers, the release and absorption of the active ingredient are further promoted.

[0064] In some embodiments, the mucoadhesive agent may include at least one of chitosan and carbomer. These mucoadhesive agents not only have biological adhesiveness and can improve the adhesion ability of the oral adhesive sheet 10, but also can promote the absorption of active pharmaceutical ingredients in the oral mucosa.

[0065] In some embodiments, the weight percentage of the diluent may be 100 to 150 parts, and may be any weight percentage between 100 and 150 parts, including 100 parts and 150 parts. The weight percentage of the diluent is controlled within this range, so that the oral adhesive sheet 10 has a suitable tablet weight, and improves the water absorption of the oral adhesive sheet, and is combined with components such as mucosal absorption enhancers and osmotic pressure enhancers to further promote the release of the active ingredients of the drug.

[0066] In some embodiments, the diluent may include at least one of dextrose, lactose, povidone K30, maltodextrin, compressible lactose, sucrose powder, and compressible starch. These diluents are aqueous diluents that can further promote the dissolution and release of the active pharmaceutical ingredient in the substrate 11.

[0067] In some embodiments, the weight percentage of the binder can be 64 to 96 parts, and can be any weight percentage between 64 and 96 parts, including 64 and 96 parts. By controlling the content of the binder within this range, the hardness, friability and other properties of the oral adhesive sheet 10 are further improved, and the release and absorption of the active pharmaceutical ingredient are further promoted in combination with other components in the oral adhesive sheet 10.

[0068] In some embodiments, the binder may include at least one of alginic acid, low-substituted hydroxypropyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone K30, cross-linked polyvinylpyrrolidone, dextrin, and lactose.

[0069] In some embodiments, the weight percentage of the osmotic pressure enhancer can be 64 to 96 parts, and can be any weight percentage between 64 and 96 parts, including 64 parts and 96 parts. By controlling the weight percentage of the osmotic pressure enhancer within this range, the water absorption of the substrate 11 is further improved, the osmotic pressure of the active pharmaceutical ingredient is increased, and the release and absorption of the active pharmaceutical ingredient are promoted.

[0070] In some embodiments, the osmotic pressure enhancer may include at least one of sodium sulfate, xylitol, mannitol, sodium chloride, lactose, sodium phosphate, and sucrose.

[0071] In some embodiments, the weight percentage of the glidant can be 2.0 to 3.0 parts, and can be any weight percentage between 2.0 and 3.0 parts, including 2.0 parts and 3.0 parts. In the exemplary embodiment, the glidant can include at least one of silicon dioxide, micropowder silica gel, and microcrystalline cellulose. These glidants have a good flow-aiding effect, which helps to improve the fluidity of powders and particles during tableting and reduce the weight difference of the tablets. Controlling the weight percentage of the glidant within this range further reduces the weight difference of the oral adhesive tablet 10 and improves the uniformity of the content of the active pharmaceutical ingredient in the oral adhesive tablet.

[0072] In some embodiments, the weight percentage of the lubricant can be 4.0 to 6.0 parts, and can be any weight percentage between 4 and 6 parts, including 4 parts and 6 parts. In the exemplary embodiment, the lubricant can include at least one of sodium stearate, magnesium stearate, and sodium stearyl fumarate. The addition of the lubricant can effectively improve the quality of the substrate 11, such as reducing the weight difference of the tablets, improving the uniformity of the content of the active ingredient of the drug, and reducing the sticking during tableting, thereby improving the tablet shape and appearance quality and production efficiency of the tablets.

[0073] In some embodiments, the base sheet 11 may further contain a flavoring agent, and the weight percentage of the flavoring agent may be 2.2 to 3.5 parts, and may be any weight percentage between 2.2 and 3.5 parts, including 2.2 parts and 3.5 parts. In an exemplary embodiment, the flavoring agent may include at least one of sucralose, menthol, and passion fruit essence.

[0074] It should be noted that the flavoring agent may be one, two or more. In a further embodiment, the oral adhesive sheet 10 may include three flavoring agents: flavoring agent I, flavoring agent II and flavoring agent III. In the exemplary embodiment, the weight portion of flavoring agent I may be 1.0 to 1.5 parts; the weight portion of flavoring agent II may be 0.6 to 1.0; the weight portion of flavoring agent III may be 0.6 to 1.0 parts. Among them, flavoring agent I may be sucralose, flavoring agent II may be menthol, and flavoring agent III may be passion fruit essence.

[0075] The addition of flavoring agents can further improve the taste and smell of the oral adhesive sheet 10 and enhance patient compliance.

[0076] In some embodiments, the mass ratio of the substrate 11 to the protective layer 12 can be (95-98): (2-5), optionally (95-97): (3-5), (96-98): (2-4). In the exemplary embodiment, the mass ratio of the substrate 11 to the protective layer 12 can be 95:5, 96:4, 97:3, 98:2, etc., which are typical but non-limiting values, or any value between any two numerical ranges. By controlling the mass ratio of the substrate 11 to the protective layer 12 within this range, the barrier effect of the protective layer 12 on the release of the active pharmaceutical ingredient can be further improved while reducing the thickness of the protective layer 12.

[0077] In some embodiments, the protective layer 12 may include a film-forming material, and the film-forming material may include at least one of ethyl cellulose, methyl cellulose, and low-permeability eutectic. These film-forming materials have good film-forming properties, and after film formation, they can effectively reduce or block the release of the active pharmaceutical ingredient in the substrate 11 from the first surface 111.

[0078] In some embodiments, the weight percentage of the film-forming material may be 15 to 40 parts, and may be any value between 15 and 40 parts, including 15 and 40 parts. By controlling the weight percentage of the film material within this range, the barrier effect of the protective layer 12 on the release of the active pharmaceutical ingredient is further improved, while reducing the thickness of the protective layer 12.

[0079] In some embodiments, the weight of the oral adhesive sheet 10 may be 0.41 g, wherein the weight of the base sheet 11 may be 0.4 g, and the weight of the protective layer 12 may be 0.01 g. The base sheet 11 of the oral adhesive sheet 10 may include the following components in parts by weight: 300 parts of erdosteine, 40 parts of benproperine phosphate, 5 parts of olopatadine hydrochloride, 0.1 parts of procaterol hydrochloride, 124.9 parts of diluent compressible lactose, 80 parts of mucosal absorption promoter lecithin, 80 parts of mucosal adhesion agent chitosan, 80 parts of adhesive low-substituted hydroxypropyl cellulose, 80 parts of osmotic pressure promoter xylitol, 2.4 parts of glidant micropowder silica gel, 4.8 parts of lubricant calcium stearate, 1.2 parts of flavoring agent sucralose, 0.8 parts of flavoring agent menthol, and 0.8 parts of flavoring agent passion fruit essence. The protective layer 12 may include 20 parts of film-forming material ethyl cellulose.

[0080] The content of the active pharmaceutical ingredients contained in the oral adhesive tablet 10 varies greatly, for example, the content of erdosteine ​​in the oral adhesive tablet 10 is 0.15 g, the content of benproperine phosphate is 0.020 g, the content of olopatadine hydrochloride is 2.5 mg, and the content of procaterol hydrochloride is 50 μg. The composition of the oral adhesive tablet 10 is controlled within this range, so that the weight difference of the oral adhesive tablet 10 is small, the content uniformity is good, and the tablets have high adhesion and expansion rate. At the same time, the release rate of the active pharmaceutical ingredients and the transdermal absorption rate are fast, and at different time points, different active pharmaceutical ingredients can be released at a relatively stable ratio.

[0081] In a fourth aspect, the present invention provides a method for preparing a pharmaceutical preparation. The method for preparing a pharmaceutical preparation in the present invention comprises the following steps:

[0082] The pharmaceutical composition and pharmaceutically acceptable excipients are prepared according to the preparation process of pharmaceutical preparations to obtain pharmaceutical preparations.

[0083] Since the above-mentioned pharmaceutical composition has good expectorant effect and antitussive effect, the pharmaceutical preparation prepared by the pharmaceutical composition preparation method of the embodiment of the present application has good antitussive and expectorant effects.

[0084] In some implementations, the pharmaceutical preparation is the oral adhesive tablet 10 described above, and the preparation process comprises the following steps:

[0085] Step S10: mixing erdosteine, benproperine phosphate, olopatadine hydrochloride, procaterol hydrochloride, a mucosal absorption enhancer, a mucosal adhesion agent, a diluent, a binder, an osmotic pressure enhancer, a glidant and a lubricant according to a proportion to obtain a total mixed powder, and tableting the total mixed powder to obtain a substrate 11;

[0086] Step S20 : ​​forming a protective layer 12 on one side of the base sheet 11 to obtain an oral adhesive sheet 10 .

[0087] In the method for preparing an oral adhesive tablet of the embodiment of the present application, four active pharmaceutical ingredients of erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride are dispersed in a substrate 11, and a protective layer 12 is formed on the deep arc surface of the substrate 11, which effectively ensures that all active pharmaceutical ingredients in the substrate 11 are released through the plane away from the protective layer 12, absorbed into the blood through the oral mucosa, and quickly exert the therapeutic effect of the drug, and fully avoid the active pharmaceutical ingredients from being absorbed through the esophagus and gastrointestinal tract. In addition, the method for preparing an oral adhesive tablet of the embodiment of the present application has few preparation process steps, and the process conditions are controllable, which is conducive to large-scale industrial production.

[0088] Step S10:

[0089] In step S10 , the drug raw materials and auxiliary materials contained in the base sheet 11 are mixed to obtain a total mixed powder, which is then tableted to obtain the base sheet 11 .

[0090] In some embodiments, the base sheet 11 also includes a flavoring agent.

[0091] In some embodiments, the mixing process includes the following steps:

[0092] Step S11: erdosteine, benproperine phosphate, olopatadine hydrochloride, a mucosal absorption enhancer, a mucosal adhesive, a diluent, a binder, an osmotic pressure enhancer, a glidant and a lubricant are mixed according to a ratio to obtain a premixed powder;

[0093] Step S12: dissolving Procaterol hydrochloride and a flavoring agent in a solvent to obtain a mixed solution of Procaterol hydrochloride and the flavoring agent;

[0094] Step S13: subjecting the mixed solution of Procaterol hydrochloride and the flavoring agent to a second mixing treatment with the premixed powder, drying, granulating, adding a glidant and a lubricant, and mixing to obtain a mixed powder.

[0095] Through the first mixing process and the second mixing process, as well as the drying, granulation and total mixing processes, the mixing uniformity and fluidity of the total mixed powder are effectively improved, thereby improving the quality of the substrate 11.

[0096] Step S20:

[0097] In step S20, a protective layer 12 is formed on one side surface of the base sheet 11, and the protective layer 12 is bonded to the base sheet 11 to obtain an oral adhesive sheet.

[0098] In some implementations, the film-forming material described above can be filled on one side of the substrate 11, and after secondary stamping, a protective layer 12 is formed on the deep arc surface of the substrate 11 to obtain the oral adhesive sheet 10. The protective layer 12 is formed on one side of the substrate 11 through secondary stamping, and the flat surface can better fit the oral mucosa, avoiding the introduction of solvents in the process of forming the protective layer 12, and reducing the influence of the solvent on the substrate 11.

[0099] In some embodiments, a film-forming material may be used to coat one side of the base sheet 11 to form a protective layer 12 to obtain an oral adhesive sheet 10 .

[0100] In some embodiments, the film-forming material described above can be dissolved in a solvent to prepare a coating solution, the substrate 11 is placed in a mold on a conveyor belt, the coating solution is sprayed above the substrate 11 with the deep arc facing upward, and then dried in a tunnel oven until all the coating solution covers the upper surface of the substrate to form a protective layer 12, thereby obtaining an oral adhesive tablet 10. In an exemplary embodiment, the solvent for preparing the coating solution may include at least one of ethanol, methyl acetate, and ethyl acetate, the concentration of the coating solution may be 16%, and the weight gain of the tablet after coating may be 2% to 5%, which may be 2.5%, 3%, 4%, and other typical but non-limiting values. The protective layer 12 is formed on the surface of the substrate 11 by coating treatment, which not only makes the weight gain of the tablet easy to control, but also further improves the uniformity of the protective layer 12 film.

[0101] In order to enable the above implementation details and operations of the present application to be clearly understood by those skilled in the art, as well as to significantly demonstrate the improved performance of the pharmaceutical composition and its application in the embodiments of the present application, the above technical scheme is illustrated by multiple embodiments below.

[0102] 1. Pharmaceutical composition

[0103] Example A1

[0104] The present embodiment provides a pharmaceutical composition. The pharmaceutical composition of the present embodiment includes erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride. The pharmaceutical composition of the present embodiment contains 1500g of erdosteine, 200g of benproperine phosphate, 25g of olopatadine hydrochloride and 0.5g of procaterol hydrochloride, and the mass ratio of erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride is 300:40:5:0.1.

[0105] 2. Oral adhesive tablet and preparation method thereof

[0106] Example B1

[0107] This embodiment provides an oral adhesive tablet, which includes the pharmaceutical composition of embodiment A1. The prescription of the oral adhesive tablet of this embodiment is shown in Table 1 below.

[0108] Table 1

[0109] Raw material name weight By weight (parts) Erdosteine 1500g 300 Benproperine phosphate 200g 40 Olopatadine 25g 5 Procaterol Hydrochloride 0.5g 0.1 Compressible lactose 624.5g 124.9 Xylitol 400g 80 Low substituted hydroxypropyl cellulose 400g 80 Lecithin 400g 80 Chitosan 400g 80 Ethyl cellulose 100g 20 Micro powder silica gel 12g 2.4 Calcium stearate 24g 4.8 Sucralose 6g 1.2 Menthol 4g 0.8 Passion fruit flavor 4g 0.8

[0110] 10,000 pieces were made.

[0111] The preparation method of the oral adhesive tablet of this embodiment comprises the following steps:

[0112] Step S1: premixing. First, erdosteine, benproperine phosphate, olopatadine, chitosan, lecithin, compressible lactose, low-substituted hydroxypropyl cellulose and xylitol in prescribed amounts are passed through a 100-mesh sieve and mixed evenly to obtain a premixed powder.

[0113] Step S2: Total mixing. Add 70% ethanol to 100 ml of Procaterol hydrochloride, passion fruit essence, sucralose and menthol to make a 14% 70% ethanol solution, and mix evenly. Spray the solution evenly into the premixed powder, mix evenly, dry at low temperature, sieve through a 20-mesh sieve, add micro-powder silica gel and calcium stearate through a 100-mesh sieve, and mix for 30 minutes to obtain the total mixed powder.

[0114] Step S3: tableting. The total mixed powder in the above step S2 is pressed into a 10.5 mm tablet with one side being a deep arc and the other side being a flat surface, and the filling is adjusted to a base tablet weight of 0.40 g, and then ethyl cellulose is filled on the deep arc surface of the base tablet for a second time, and then deep arc tableting is performed for a second time to a tablet weight of 0.41 g / tablet (the mass ratio of the base tablet to the protective layer is about 97.6:2.4), so as to obtain the oral adhesive tablet of this embodiment.

[0115] Example B2

[0116] This embodiment provides an oral adhesive tablet, and the formulation of the oral adhesive tablet of this embodiment is the same as that of the oral adhesive tablet of Example B1. The preparation method of the oral adhesive tablet of this embodiment comprises the following steps:

[0117] Step G1: Preparation of substrate: The preparation method of the substrate in the oral adhesive tablet of this embodiment is the same as the preparation method of the substrate in Example B1.

[0118] Step G2: Preparation of coating solution: Take the prescribed amount of micronized ethyl cellulose and dissolve it in 95% ethanol, disperse it evenly, and prepare a solution containing 16% ethyl cellulose to obtain the coating solution of this example.

[0119] Step G3: Coating. Place the substrate in the bubble of the mold attached to the conveyor belt, and make the upper edge of the bubble slightly higher than the upper surface of the substrate by 1.0 mm, ensuring that each bubble contains one sheet, and there should be no overlapping or vertical sheets, and one side of the substrate is facing up. Control the speed of the driving shaft of the transmission belt to 2 to 3 rpm, control the preheating air outlet temperature to 40°C to 45°C, adjust the pressure and flow of the spray gun so that the sprayed coating liquid is fan-shaped and perpendicular to the running direction of the conveyor belt. Spray the coating liquid above the transmission belt, control the spray flow rate until the surface of the substrate is flat and smooth, and then dry it under the condition of an inlet air temperature of 60°C to 70°C, and cool it to room temperature by natural wind after it is transmitted, so that the substrate weight increases to 0.41g, and the oral adhesive tablet of this embodiment is obtained.

[0120] Example B3

[0121] This embodiment provides an oral adhesive tablet. The formulation and preparation method of the oral adhesive tablet of this embodiment are substantially the same as those of the oral adhesive tablet of Example B1. The difference between the oral adhesive tablet of this embodiment and the oral adhesive tablet of Example B1 is that the formulation of the oral adhesive tablet of this embodiment is that the weight of the mucosal adhesive agent chitosan in the oral adhesive tablet formulation of Example B1 is reduced to 320 g, and the weight of the diluent compressible lactose is increased to 704.5 g.

[0122] Example B4

[0123] This embodiment provides an oral adhesive tablet. The formulation and preparation method of the oral adhesive tablet of this embodiment are substantially the same as those of the oral adhesive tablet of Example B1. The difference between the oral adhesive tablet of this embodiment and the oral adhesive tablet of Example B1 is that the oral adhesive tablet of this embodiment is formulated by reducing the weight of the mucosal absorption promoter lecithin in the oral adhesive tablet formulation of Example B1 to 320 g, and increasing the weight of the diluent compressible lactose to 704.5 g.

[0124] Example B5

[0125] This embodiment provides an oral adhesive tablet. The formulation and preparation method of the oral adhesive tablet of this embodiment are substantially the same as those of the oral adhesive tablet of Example B1. The difference between the oral adhesive tablet of this embodiment and the oral adhesive tablet of Example B1 is that the formulation of the oral adhesive tablet of this embodiment is that the weight of the osmotic pressure enhancer xylitol in the formulation of the oral adhesive tablet of Example B1 is reduced to 320 g, and the weight of the diluent compressible lactose is increased to 704.5 g.

[0126] Example B6

[0127] This embodiment provides an oral adhesive tablet. The formulation and preparation method of the oral adhesive tablet of this embodiment are substantially the same as those of the oral adhesive tablet of Example B1. The difference between the oral adhesive tablet of this embodiment and the oral adhesive tablet of Example B1 is that the formulation of the oral adhesive tablet of this embodiment is that the weight of the lubricant calcium stearate in the formulation of the oral adhesive tablet of Example B1 is reduced to 19.2 g, and the weight of the diluent compressible lactose is increased to 629.3 g.

[0128] Example B7

[0129] This embodiment provides an oral adhesive tablet. The formulation and preparation method of the oral adhesive tablet of this embodiment are substantially the same as those of the oral adhesive tablet of Example B1. The difference between the oral adhesive tablet of this embodiment and the oral adhesive tablet of Example B1 is that the formulation of the oral adhesive tablet of this embodiment is that the weight of the glidant silicon dioxide in the formulation of the oral adhesive tablet of Example B1 is reduced to 9.6 g, and the weight of the diluent compressible lactose is increased to 626.9 g.

[0130] Example B8

[0131] This embodiment provides an oral adhesive tablet. The formulation and preparation method of the oral adhesive tablet of this embodiment are basically the same as those of the oral adhesive tablet of Example B1. The difference between the oral adhesive tablet of this embodiment and the oral adhesive tablet of Example B1 is that the oral adhesive tablet of this embodiment is formulated by reducing the weight of the film-forming material ethyl cellulose in the oral adhesive tablet formulation of Example B1 to 80 g, and performing secondary tablet compression to a tablet weight of 0.408 g / tablet.

[0132] Example B9

[0133] This embodiment provides an oral adhesive tablet. The formulation and preparation method of the oral adhesive tablet of this embodiment are substantially the same as those of the oral adhesive tablet of Example B1. The difference between the oral adhesive tablet of this embodiment and the oral adhesive tablet of Example B1 is that the formulation of the oral adhesive tablet of this embodiment is that the mucosal adhesive agent chitosan in the oral adhesive tablet formulation of Example B1 is replaced with carbomer, and the weight remains unchanged.

[0134] Example B10

[0135] This embodiment provides an oral adhesive tablet. The formulation and preparation method of the oral adhesive tablet of this embodiment are substantially the same as those of the oral adhesive tablet of Example B1. The difference between the oral adhesive tablet of this embodiment and the oral adhesive tablet of Example B1 is that the formulation of the oral adhesive tablet of this embodiment is that the mucosal absorption promoter lecithin in the formulation of the oral adhesive tablet of Example B1 is replaced with poloxamer, and the weight remains unchanged.

[0136] Example B11

[0137] This embodiment provides an oral adhesive tablet. The formulation and preparation method of the oral adhesive tablet of this embodiment are substantially the same as those of the oral adhesive tablet of Example B1. The difference between the oral adhesive tablet of this embodiment and the oral adhesive tablet of Example B1 is that the formulation of the oral adhesive tablet of this embodiment is that the osmotic pressure enhancer xylitol in the formulation of the oral adhesive tablet of Example B1 is replaced with sodium chloride, and the weight remains unchanged.

[0138] Example B12

[0139] This embodiment provides an oral adhesive tablet. The formulation and preparation method of the oral adhesive tablet of this embodiment are substantially the same as those of the oral adhesive tablet of Example B1. The difference between the oral adhesive tablet of this embodiment and the oral adhesive tablet of Example B1 is that the formulation of the oral adhesive tablet of this embodiment is that the film-forming material in the formulation of the oral adhesive tablet of Example B1 is replaced with Eutectic RS30D, and the weight remains unchanged.

[0140] Comparative Example B1

[0141] This embodiment provides an oral adhesive tablet. The formulation and preparation method of the oral adhesive tablet of this embodiment are substantially the same as those of the oral adhesive tablet of Example B1. The difference between the oral adhesive tablet of this embodiment and the oral adhesive tablet of Example B1 is that the oral adhesive tablet of this embodiment is formulated by removing the mucosal adhesive chitosan in the oral adhesive tablet formulation of Example B1, and increasing the weight of the diluent compressible lactose to 1024.5 g.

[0142] Comparative Example B2 This example provides an oral adhesive tablet. The formulation and preparation method of the oral adhesive tablet of this example are substantially the same as those of the oral adhesive tablet of Example B1. The difference between the oral adhesive tablet of this example and the oral adhesive tablet of Example B1 is that the oral adhesive tablet of this example is formulated by removing the mucosal absorption promoter lecithin from the oral adhesive tablet of Example B1, and increasing the weight of the diluent compressible lactose to 1024.5 g.

[0143] Comparative Example B3 This example provides an oral adhesive tablet. The formulation and preparation method of the oral adhesive tablet of this example are substantially the same as those of the oral adhesive tablet of Example B1. The difference between the oral adhesive tablet of this example and the oral adhesive tablet of Example B1 is that the oral adhesive tablet of this example is formulated by removing the osmotic pressure enhancer xylitol from the oral adhesive tablet formulation of Example B1, and increasing the weight of the diluent compressible lactose to 1024.5 g.

[0144] Comparative Example B4 This embodiment provides an oral adhesive tablet. The formulation and preparation method of the oral adhesive tablet of this embodiment are basically the same as those of the oral adhesive tablet of Example B1. The difference between the oral adhesive tablet of this embodiment and the oral adhesive tablet of Example B1 is that the oral adhesive tablet of this embodiment is formulated by removing the glidant micropowder silica gel in the oral adhesive tablet formulation of Example B1, and the weight of the diluent compressible lactose is increased to 636.5g.

[0145] Comparative Example B5 This example provides an oral adhesive tablet. The formulation and preparation method of the oral adhesive tablet of this example are substantially the same as those of the oral adhesive tablet of Example B1. The difference between the oral adhesive tablet of this example and the oral adhesive tablet of Example B1 is that the oral adhesive tablet of this example is formulated by deleting the lubricant calcium stearate in the oral adhesive tablet formulation of Example B1, and increasing the weight of the diluent compressible lactose to 648.5 g.

[0146] Comparative Example B6 This embodiment provides an oral adhesive sheet. The formulation and preparation method of the oral adhesive sheet of this embodiment are substantially the same as those of the oral adhesive sheet of Example B1. The difference between the oral adhesive sheet of this embodiment and the oral adhesive sheet of Example B1 is that the oral adhesive sheet formulation of this embodiment is obtained by removing the film-forming material in the oral adhesive sheet formulation of Example B1, and removing the protective layer in the oral adhesive sheet.

[0147] 3. Investigation of the activity of the drug composition

[0148] 3.1. Investigation of antitussive efficacy

[0149] (1) Experimental animals and experimental environment: 48 guinea pigs, all male, 3-5 weeks old, of normal grade, weighing 280-320 g, were fed with normal feed, maintained at room temperature of 22-24°C, relative humidity of 58%, and a lighting condition of 12 h light / 12 h dark cycle. They were allowed to eat and drink freely.

[0150] (2) Reagents: lipopolysaccharide; capsaicin; Tween-80 solution; anhydrous ethanol;

[0151] (3) Instrument: Ultrasonic nebulizer

[0152] (4) Medicines

[0153] Take the oral adhesive tablet of Example B1 and the positive control drug benproperine phosphate tablet (20 mg / tablet) respectively and grind them into powder. Take appropriate amount of the ground oral adhesive tablet powder of Example B1 and benproperine phosphate tablet powder (both are approximately equivalent to 26.6 mg of benproperine phosphate), put them into 1000 ml volumetric bottles, add water to dissolve, make up to volume, shake well, and obtain the Example B1 test solution and benproperine phosphate tablet solution.

[0154] (5) Experimental methods:

[0155] 1) Animal modeling, grouping and drug administration:

[0156] After 3 days of adaptive feeding of experimental animals, 8 guinea pigs were randomly selected as blank control group, and the remaining guinea pigs were used to establish bronchitis cough model. The specific operation of establishing bronchial cough model is as follows: after the animals are adapted to the environment, after anesthesia of each group of guinea pigs on the first day, 200 μL of LPS (1g / L) was given through endotracheal intubation, and conventional feeding was continued for 21 days. On the 22nd day, the guinea pigs with successful modeling were randomly divided into model group, high-dose group of pharmaceutical composition of Example A1, low-dose group of pharmaceutical composition of Example A1, high-dose group of positive control, and low-dose group of positive control, as shown in Table 2, with 8 in each group. The administration of each group was based on the daily dosage recommended by adult clinical practice, and the dosage of guinea pigs was converted into the dosage according to the body mass coefficient, and the model group was gavaged with purified water. Each group was administered once daily, as shown in Table 2. The model group was administered distilled water 2.0 ml / kg by gavage, the high-dose and low-dose groups of Example B1 were administered the test solution of Example B1 2.0 ml / kg and 1.0 ml / kg by gavage, respectively, and the high-dose and low-dose groups of the positive control were administered the solution of benproperine phosphate tablets (20 mg / tablet) 2 ml / kg and 1 ml / kg by gavage, respectively.

[0157] Each group was treated once a day for 5 consecutive days. On the 6th day, each group was given capsaicin stimulation to induce cough. The specific operation was as follows: 30.5 mg of capsaicin was taken, 1 mL of Tween-80 solution and 1 mL of anhydrous ethanol were added, and 8.0 mL of normal saline were added to make a 0.01 mol / L capsaicin mother solution. 1 mL of the capsaicin mother solution was taken and diluted to 50 mL to make 2×10 -4 Guinea pigs were placed in a transparent wide-mouth plastic bottle, and coughing was induced by exposing each guinea pig to the vapor of a capsaicin solution (0.2 mmol / L) for 15 s using an ultrasonic nebulizer.

[0158] 2) Observation of cough sensitivity in guinea pigs:

[0159] After the intervention, the guinea pigs' cough latency and the number of coughs within 3 minutes were recorded. The following two phenomena were considered signs of coughing: changes in the guinea pigs' posture, such as opening the mouth, tilting the forelimbs, and stretching the neck forward; and the sound of the guinea pigs' coughing. The number of coughs and cough latency were recorded by 3 independent observers. The results are shown in Table 2.

[0160] Table 2

[0161] Group Drug solution gavage volume Cough latency period / s Number of coughs / times Blank Group / 47.93±12.56 2.73±0.89 Model Group water 25.27±4.78 4.62±0.74 Example B1 High-dose group of pharmaceutical composition Example B1 Test solution 2.0 ml / kg 47.34±8.71 2.77±0.47 Example B1 Low-dose group of pharmaceutical composition Example B1 Test solution 1.0 ml / kg 45.39±12.72 2.75±0.38 Positive control high dose group Benproperine phosphate tablet solution 2.0ml / kg 44.63±6.38 2.88±5.65 Positive control low dose group Benproperine phosphate tablet solution 1.0ml / kg 40.17±5.75 2.97±4.37

[0162] As shown in Table 2, in the cough sensitivity experiment, compared with the high-dose group of benproperine phosphate, the cough latency of the guinea pigs in the high-dose group of the pharmaceutical composition of Example B1 was significantly prolonged, the number of coughs was significantly reduced, and the cough latency and cough number of the guinea pigs in the high-dose group of the pharmaceutical composition of Example B1 were similar to those of the blank control group. Compared with the low-dose group of benproperine phosphate, the cough latency of the guinea pigs in the low-dose group of the pharmaceutical composition of Example B1 was also significantly prolonged, and the number of coughs was also significantly reduced. It can be seen from this that the antitussive effect of the pharmaceutical composition of Example B1 on guinea pigs is significantly better than that of benproperine phosphate, which shows that the four active ingredients of erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride in the pharmaceutical composition provided in the examples of the present application have a synergistic effect with each other, which can further improve the antitussive effect of the pharmaceutical composition.

[0163] 3.2. Investigation of expectorant efficacy

[0164] Take the oral adhesive tablet of Example B1 and erdosteine ​​tablets (150 mg / tablet) respectively, put them in a mortar and grind them finely. Accurately weigh an appropriate amount of the oral adhesive tablet of Example B1 and an appropriate amount of the positive control drug erdosteine ​​tablet powder (equivalent to 26.6 mg of erdosteine), put them in a 100 ml volumetric bottle, add water to dissolve, make up to volume, and shake well to prepare the Example B1 test solution and erdosteine ​​reference solution.

[0165] Rabbits were divided into three groups: blank group, Example B1 group and positive control drug erdosteine ​​group, 10 in each group. The experimental group was gavaged with the above-mentioned Example B1 test solution according to the dosage of 1mL / kg, the positive control group was gavaged with the above-mentioned erdosteine ​​tablet positive control solution according to the dosage of 1mL / kg, and the blank group rabbits were gavaged with the same volume of distilled water. After 6 hours, urethane was anesthetized, the back position was 20 degrees, the head was fixed in a low position, the skin of the front whisker was cut to expose the trachea, and a Y-shaped endotracheal tube was inserted. One end of the cannula was connected to a regulator to inhale air with constant temperature and humidity, and the other end was connected to a test tube with a scale to collect the outflowing respiratory fluid, and the collection time was 24 hours. The respiratory fluid collection amount of each group of rabbits is as shown in Table 3.

[0166] Table 3

[0167] Group Rabbit respiratory tract fluid collection volume (ml / kg) Blank Group 2.84±0.21 Experimental group (administered with the oral adhesive tablet of Example B1) 3.53±0.24 Positive control group (administered erdosteine ​​tablet solution) 3.12±0.26

[0168] As shown in Table 3, in the experiment of the amount of liquid outflow from the respiratory tract, the amount of liquid outflow from the respiratory tract of the rabbits in the experimental group given the oral adhesive tablet solution of Example B1 by gavage was significantly increased compared with that in the control group given the erdosteine ​​solution by gavage, which indicates the synergistic effect of the antitussive drug benproperine phosphate, the expectorant erdosteine, the H1 receptor antagonist olopatadine and the smooth muscle relaxant procaterol hydrochloride used in combination in the pharmaceutical composition of the examples of the present application.

[0169] Erdosteine ​​is mainly used for cough and sputum caused by respiratory tract infection. It is a mucolytic expectorant and a prodrug. It mainly breaks the disulfide bonds of mucin in bronchial secretions through metabolites containing free sulfhydryl groups, changes its composition and rheological properties, and thus facilitates the discharge of sputum and makes more sputum discharged from the respiratory tract. It also has the effect of enhancing the motility of mucociliary cells. Benproperine phosphate is a strong non-addictive antitussive drug that has the effect of reducing the impulse of lung traction receptors and reducing the excitability of the cough center. It is clinically used to treat acute and chronic bronchitis and cough caused by various stimuli. Olopatadine is an antihistamine that has a selective antagonistic effect on histamine H1 receptors, inhibits the production and release of chemical transmitters (leukotrienes, thromboxanes, PAF, etc.), and has an inhibitory effect on the release of the neurotransmitter tachykinin. It is currently recognized by clinical physicians as a significantly effective drug for the treatment of post-infection cough, and is also the primary treatment drug recommended by domestic guidelines. It can reduce bronchial sensitivity, thereby relieving bronchial inflammation and effectively alleviating cough symptoms.

[0170] The pharmaceutical composition of the embodiment of the present application uses four active ingredients, namely, benproperine phosphate, erdosteine, olopatadine, and procaterol hydrochloride, in combination, so that there is a synergistic effect between the four active ingredients of the medicine, which can effectively improve the antitussive and expectorant effects of the pharmaceutical composition, and has a good effect on treating cough and sputum caused by colds and respiratory infections.

[0171] 4. Quality inspection of oral adhesive tablets:

[0172] 4.1. In vitro adhesion ability assay

[0173] Test method: Use Figure 4 The adhesion force was measured using the homemade device shown in the figure. Figure 4 As shown, one side of the upper plastic sheet 01 is fixed on the iron frame, and the other side is used to fix the biofilm material 02; one side of the lower plastic sheet 04 is used to fix the oral adhesive sheet 03, and the other side is connected to the thin plastic bag 05. Eggshell membrane is selected as the biofilm material 02, and after soaking in artificial saliva for 45 minutes, a small square of 2cm×2cm is cut and adhered to the upper plastic sheet with a strong double-sided tape.

[0174] Take 6 oral adhesive tablets of the drug to be tested prepared in each embodiment, 1 tablet each time, fix the single-sided protective layer of the oral adhesive tablet to the lower plastic sheet 04 with a strong double-sided tape, moisten the side of the oral adhesive tablet without a protective layer with artificial saliva, and quickly stick it to the egg membrane, while continuously applying an external force of 10g for 5min, then slowly drip purified water into the plastic bag 05 with a 10mL graduated pipette, and record the volume of water used when the adhesive sheet falls off. The adhesion force is expressed as the sum of the masses (g) of water, the lower plastic sheet 04 and the plastic bag 05.

[0175] The in vitro adhesion test results of the oral adhesive sheets of various examples are shown in Table 4.

[0176] Table 4

[0177]

[0178] As shown in Table 4, the oral adhesive tablets of Examples B1 to B12 all have high in vitro adhesion, among which the oral adhesive tablet of Example B1 has the highest in vitro adhesion, and the average in vitro adhesion of the oral adhesive tablets of Examples B1, B2, B4 to B12 is greater than 180 g. The adhesion of the oral adhesive tablet of Example B3 is reduced due to the reduction of the content of chitosan, a mucosal adhesive agent in the prescription. Since the lubricant and glidant are reduced in Examples B5 and B6, respectively, the relative standard deviations of their adhesion increase to varying degrees. The relative standard deviations of the adhesion of Comparative Examples B4 and B5 are further increased due to the lack of lubricants and glidants.

[0179] In the oral adhesive tablet of Comparative Example B1, due to the lack of chitosan, a mucosal adhesive agent, its in vitro adhesion is greatly reduced. Compared with the oral adhesive tablet of Example B1, although the content of chitosan, a mucosal adhesive agent, in the oral adhesive tablet of Comparative Example B5 remains unchanged, the lubricant is removed from the prescription, resulting in reduced adhesion, which may be because the lack of lubricant increases the hydrophilicity of the substrate, and the external adhesion of the oral adhesive tablet of Comparative Example B5 is also significantly reduced.

[0180] 4.2 Determination of in vitro swelling

[0181] Test method: Take 6 oral adhesive tablets of each embodiment or comparative example, put them into the rotating basket of the dissolution instrument, and weigh the initial mass. Put the rotating basket into the dissolution cup containing 0.9L artificial saliva, keep the constant temperature (37±0.1)℃ with a water bath, and rotate at 100r / min. Take out each group of oral adhesive tablets at 2min, 10min, 30min, 60min, 90min, 120min, 240min, 480min, 960min, and 1440min after the start of the experiment, absorb the moisture around the basket with filter paper, and weigh it. Calculate the swelling degree (mg) of each adhesive tablet at different times by the mass change, and express it as the mass difference value exceeding 0 point after swelling at each time point. The results are shown in Tables 5 and 6.

[0182] Table 5

[0183]

[0184] Table 6

[0185]

[0186]

[0187] As shown in Tables 5 and 6, the 24-hour in vitro swelling degree of the oral adhesive sheet of Example B1 was slightly higher than that of Example B4 in which the mucosal absorption enhancer was reduced and Comparative Examples B2 and B3 in which the mucosal absorption enhancer and the osmotic pressure enhancer were removed. The in vitro swelling degree of Example B2 did not change significantly; Example B3 reduced the amount of chitosan, a mucosal adhesive, and its in vitro swelling degree increased significantly; Example B4 reduced the amount of mucosal absorption enhancer, and its in vitro swelling degree was slightly lower than that of Example B1; Example B5 reduced the amount of osmotic pressure enhancer, and its in vitro swelling degree did not change significantly; Example B6 reduced the amount of water-insoluble flow enhancer. In Example B7, the amount of lubricant calcium stearate was reduced, and its in vitro swelling degree did not change significantly; in Example B8, the amount of ethyl cellulose used as the film-forming material for preparing the protective layer was reduced to 80 g, and the in vitro swelling degree did not change significantly; in Example B9, the mucosal adhesive was replaced with carbomer, and the in vitro swelling degree was significantly increased; in Example B10, the mucosal absorption promoter was replaced with poloxamer, in Example B11, the osmotic pressure promoter was replaced with sodium chloride, and in Example B12, the film-forming material for preparing the protective layer was changed to Eudragit RS30D, and there was no significant change in the in vitro swelling degree. Comparative Example B1 removed the mucosal adhesive, and the in vitro swelling degree was significantly improved after 24 hours; Comparative Example B2 removed the mucosal absorption promoter, and its in vitro swelling degree was significantly lower than that of Example B1; Comparative Example B3 removed the osmotic pressure promoter, and its in vitro swelling degree was the same as that of Comparative Example B2; Comparative Example B4 removed the glidant micropowder silica gel, and the in vitro swelling degree also increased significantly; Comparative Example B5 removed the lubricant, and the in vitro swelling degree increased significantly; Comparative Example B6 removed the protective layer, and its in vitro swelling degree was significantly increased.

[0188] The in vitro swelling degree of the examples of the present application is relatively low, which proves that the formulation and preparation method of the examples of the present application can well maintain the active ingredients to avoid diffusion through non-adhesive surfaces and absorption through the gastrointestinal tract, thereby being destroyed by digestive enzymes and liver enzymes.

[0189] 4.3. Weight difference determination

[0190] Test method: Take 20 test pieces, accurately weigh the total weight, calculate the average piece weight, and then accurately weigh each piece. The results of the weight difference measurement of the oral adhesive pieces of each embodiment are shown in Table 7.

[0191] Table 7

[0192]

[0193] As shown in Table 7, the relative standard deviation of the weight of the oral adhesive tablets of Examples B1 to B5, and Examples B8 to B12 is small; the difference in tablet weight increases in Examples B6 and B7 due to the reduction in the content of glidant and lubricant. However, the relative standard deviation of the tablet weight of the oral adhesive tablets of Comparative Examples B4 and B5 greatly increases due to the lack of glidant and lubricant, and is greater than 10%.

[0194] 4.4. Determination of the uniformity of the content of Procaterol Hydrochloride

[0195] Test method: 10 tablets of this product are placed in 10ml volumetric bottles, 5ml of mobile phase is added, and the product is shaken for 10 minutes to dissolve the Procaterol hydrochloride. The product is diluted to the mark with the mobile phase, shaken well, filtered, and the filtrate is taken as the test solution; another amount of Procaterol hydrochloride reference substance is taken, accurately weighed, dissolved in the mobile phase, and quantitatively diluted to make a solution containing 5μg per 1ml as the reference substance solution. The content is determined according to the method under the content determination item, and the relative content X of each single dose is calculated with the labeled amount as 100, and the mean X and standard deviation S as well as the absolute value of the difference between the labeled amount and the mean A=|100-X| are calculated.

[0196] If A+2.2S<15, the content uniformity of the test sample meets the requirements;

[0197] If A+S>15, it does not meet the requirements;

[0198] If A+2.2S>15, and A+S<15, another 20 samples of the test sample should be retested. Based on the initial and retest results, calculate the mean X, standard deviation S, and the absolute value A of the difference between the labeled amount and the mean of the 30 single doses. Then calculate and determine according to the following formula. When A<3.75, if A2+S2<3.752, the content uniformity of the test sample meets the requirements; if A2+S2>3.752, it does not meet the requirements. When A>3.75, if A+1.7S<15, the content uniformity of the test sample meets the requirements; if A+1.7S>15, it does not meet the requirements.

[0199] The results of the uniformity test of the content of Procaterol hydrochloride in the oral adhesive tablets of each example are shown in Table 8.

[0200] Table 8

[0201]

[0202] In Example B1 to Example B12 and Comparative Example B1 to Comparative Example B6 oral adhesive tablets, the prescription amount of Procaterol hydrochloride per 10,000 tablets is 0.5 g, the content of Procaterol hydrochloride in each tablet is 50 μg, which is much lower than 20 mg, and the percentage of Procaterol hydrochloride is 0.025%, which is much lower than 25%. According to the relevant provisions of the "Chinese Pharmacopoeia", content uniformity control is required.

[0203] As shown in Table 8, the content uniformity test results of the oral adhesive tablets of Examples B1 to B5, and Examples B8 to B12 are all at a high level. The content uniformity of the oral adhesive tablets of Examples B6 and B7 is slightly reduced due to the change in the content of the lubricant and the glidant, but it is still within the qualified range. The content uniformity of the oral adhesive tablets of Comparative Examples B4 and B5 is greatly reduced due to the lack of lubricants and glidants, especially the content uniformity A+2.2S value of Procaterol Hydrochloride in the oral adhesive tablet of Comparative Example B4 is greater than 15.

[0204] 4.5 Release Determination

[0205] Determination method:

[0206] The oral adhesive tablets of a pharmaceutical composition for treating cough with phlegm caused by cold and respiratory tract infection prepared in the examples and comparative examples were tested according to the paddle method specified in the Pharmacopoeia of the People's Republic of China (General Rules of Part Four, 2020 Edition 0931). The temperature was (37±0.5)°C, the dissolution medium was 100mL artificial saliva, the rotation speed was 100r / min, and 2ml of the solution was taken at 2, 10, 30, 60, 90, 120, 240, 480, 960, and 1440min, filtered, and the filtrate was taken as the test solution.

[0207] Take the above test solution, determine the dissolution amount of erdosteine ​​with the highest content and procaterol hydrochloride with the lowest content in the test solution, and calculate the cumulative release. The erdosteine ​​dissolution determination method is in accordance with the general rule 0401 ultraviolet-visible spectrophotometry of Part IV of Ch.p2020 edition, and the absorbance is measured at a wavelength of 237nm.

[0208] The method for determining the dissolution amount of Procaterol Hydrochloride is high performance liquid chromatography, and the specific determination is as follows:

[0209] Test drugs: Procaterol hydrochloride reference substance, sodium dihydrogen phosphate (analytical grade), phosphoric acid (analytical grade), methanol (chromatographic grade), and ultrapure water were used in the experiment.

[0210] Instruments: High performance liquid chromatography, UV detector; analytical balance.

[0211] Content determination method

[0212] Chromatographic conditions: octadecylsilane bonded silica gel; phosphate buffer (take 11.04 g of sodium dihydrogen phosphate, add 1000 ml of water, and adjust the pH to 3.1±0.05 with phosphoric acid)-methanol (83:17) as the mobile phase, the detection wavelength is 259 nm, and the theoretical plate number calculated based on Procaterol hydrochloride must not be less than 2000.

[0213] Test solution: Take 2 ml of the above dissolution solution, place it in a 10 ml volumetric flask, add an appropriate amount of mobile phase, shake to dissolve, dilute to scale, shake well and filter. Take the filtrate as the test solution.

[0214] Preparation of reference solution: Accurately measure an appropriate amount of Procaterol hydrochloride reference substance, dissolve it in the mobile phase and dilute it into a solution with a concentration of 5 μg / ml as the reference solution.

[0215] Sample determination: Accurately measure 20 μl of the test solution and the reference solution, inject them into the chromatograph, and record the chromatogram; calculate by the peak area using the external standard method to obtain the result.

[0216] The cumulative release rate and release curve of erdosteine ​​in the oral adhesives of various examples and comparative examples are shown in Table 9, and the cumulative release rate and release curve of Procaterol hydrochloride in the oral adhesives of various examples and comparative examples are shown in Table 10.

[0217] Table 9

[0218]

[0219]

[0220] Table 10

[0221]

[0222] As shown in Tables 9 and 10, the cumulative release of erdosteine ​​and Procaterol hydrochloride in the oral adhesive tablet of Example B1 is high and the release rate is fast. In addition, the cumulative release of the two active ingredients, erdosteine ​​with the highest content and Procaterol hydrochloride with the lowest content, in the oral adhesive tablet of Example B1 is similar at different time points, so that the ratio of erdosteine ​​and Procaterol hydrochloride released in the oral adhesive tablet of Example B1 at different times is similar. This can further enable erdosteine ​​and Procaterol hydrochloride to be released at a relatively constant ratio at different times during the use of the oral adhesive tablet and be absorbed by the human body, thereby further promoting the synergistic effect between the four active ingredients in the oral adhesive tablet.

[0223] Compared with Example B1, the cumulative release degree and release rate of erdosteine ​​and Procaterol hydrochloride in the oral adhesive of Example B2 are similar to those of Example B1, which indicates that preparing the protective layer by secondary tableting and preparing the protective layer by coating have no obvious effect on dissolution.

[0224] Similar to Example B1, erdosteine ​​and Procaterol hydrochloride in the oral adhesive tablets of Examples B3 to B12 have similar cumulative release rates at different time points, which indicates that when the contents of erdosteine ​​and Procaterol hydrochloride are very different, and the content of erdosteine ​​is 3000 times that of Procaterol hydrochloride, the oral adhesive provided in the examples of the present application can still release erdosteine ​​and Procaterol hydrochloride at a relatively constant ratio, which helps the four active ingredients in the oral adhesive tablets of the examples of the present application to be released at a relatively constant ratio and absorbed by the human body when the oral adhesive tablets of the examples of the present application are used, thereby further promoting the synergistic effect between the four active ingredients in the oral adhesive tablets of the examples of the present application.

[0225] Since there are differences between the prescriptions of the oral adhesive tablets of Examples B3 to B12 and the prescriptions of the oral adhesive tablets of Example B1, the cumulative release and release rate of erdosteine ​​or Procaterol hydrochloride in the oral adhesive tablets of different Examples are also slightly different. Among them, compared with Example B1, the cumulative release and release rate of the active ingredients in the oral adhesive tablets of Examples B3 to B5 are significantly reduced at 480 min, and there is no significant change in the cumulative release and release rate of the active ingredients in the oral adhesive tablets of Examples B6, B7 and B12. Due to the reduction of film-forming materials in the oral adhesive tablet of Example B8, part of the active ingredients are released from one side of the protective layer, which slightly increases the dissolution rate. The cumulative release and release rate of the oral adhesive tablets of Examples B9 to B11 are slightly reduced.

[0226] Compared with Example B1, the cumulative release and release rate of the active ingredients in the oral adhesive tablets of Comparative Example B1 and Comparative Example B2 were significantly reduced. At 1440 min, the cumulative release of erdosteine ​​in the oral adhesive tablet of Comparative Example B1 was less than 60%, and the cumulative release of Procaterol hydrochloride was about 70%. The cumulative release of erdosteine ​​in the oral adhesive tablet of Comparative Example B2 was less than 80%, and the cumulative release of Procaterol hydrochloride was about 87%.

[0227] However, the difference between the cumulative release of Procaterol hydrochloride and erdosteine ​​in the oral adhesive tablets of Comparative Examples B2 to B4 is relatively large. For example, at 120 minutes, the difference between the cumulative release of Procaterol hydrochloride and the cumulative release of erdosteine ​​in the oral adhesive tablets of Comparative Examples B1 and B2 is greater than 20%; at 60 to 120 minutes, the difference between the cumulative release of Procaterol hydrochloride and the cumulative release of erdosteine ​​in the oral adhesive tablet of Comparative Example B4 is greater than 12%; at 60 minutes, the difference between the cumulative release of Procaterol hydrochloride and the cumulative release of erdosteine ​​in the oral adhesive tablet of Comparative Example B5 is about 14%. The large difference in cumulative release between Procaterol hydrochloride and erdosteine ​​results in a large difference in the proportion of the two active ingredients released at different times, which is not conducive to the absorption of the active ingredients of the drugs into the blood at a relatively constant proportion.

[0228] In the oral adhesive tablet of Comparative Example B6, due to the lack of a protective layer, both sides of the substrate can release the active pharmaceutical ingredient, thereby increasing the release rate of the active pharmaceutical ingredient.

[0229] The oral adhesive tablet of the embodiment of the present application controls the compound use of four active ingredients, promotes the synergistic effect between the four active ingredients, effectively improves the antitussive and expectorant effects, and enables the active ingredients of the drug to be concentrated and quickly absorbed into the blood through the oral mucosa, quickly exerting the antitussive, expectorant and antiasthmatic effects, and can avoid the first-pass effect of the liver produced by the liver drug enzymes and the destructive effects of the gastrointestinal digestive enzymes on the active ingredients of the drug, prolong the action time of the drug, improve the bioavailability of the drug, and can also be removed when necessary to avoid further continuation or expansion of the harm of the drug.

[0230] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride.

2. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride is (240-360): (30-60): (4-6): (0.08-0.12).

3. The pharmaceutical composition according to claim 2, characterized in that The mass ratio of erdosteine, benproperine phosphate, olopatadine hydrochloride and procaterol hydrochloride is 300:40:5:0.1; and / or The daily dosage of benproperine phosphate is 0.85714-1.7143 mg / kg.

4. Use of the pharmaceutical composition according to any one of claims 1 to 3 in the preparation of at least one of expectorant, antitussive, antiasthmatic and antihistamine drugs.

5. A pharmaceutical preparation, characterized in that The pharmaceutical preparation comprises the pharmaceutical composition according to any one of claims 1 to 3 and pharmaceutically acceptable excipients.

6. The pharmaceutical preparation according to claim 5, characterized in that The pharmaceutical preparation is an oral adhesive tablet, which includes a base sheet. The base sheet includes the following components in parts by weight: One side surface of the substrate is flat, and the other side surface is arc-shaped; and / or The oral adhesive sheet further comprises a protective layer, which is arranged on one side of the curved surface of the substrate, and the mass ratio of the substrate to the protective layer is (95-98):(2-5).

7. The pharmaceutical preparation according to claim 6, characterized in that The mucosal absorption enhancer includes at least one of poloxamer, glycofurol, lecithin, and isopropyl myristate; and / or The mucosal adhesive comprises at least one of chitosan and carbomer; and / or The diluent comprises at least one of dextrose, povidone K30, maltodextrin, compressible lactose, sucrose, and compressible starch; and / or The adhesive comprises at least one of alginic acid, low-substituted hydroxypropyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone K30, cross-linked polyvinylpyrrolidone, dextrin and lactose; and / or The osmotic pressure enhancer comprises at least one of sodium sulfate, xylitol, mannitol, sodium chloride, lactose, sodium phosphate, and sucrose; and / or The glidant comprises at least one of silicon dioxide, micro-powdered silica gel and microcrystalline cellulose; and / or The lubricant promoter includes at least one of sodium stearate, magnesium stearate, and sodium stearyl fumarate; and / or The protective layer includes 15 to 40 parts of film-forming materials, and the film-forming materials include at least one of ethyl cellulose, methyl cellulose, and low-permeability Eudragit.

8. The pharmaceutical preparation according to any one of claims 6 to 7, characterized in that The base sheet also includes 2.2 to 3.5 parts of flavoring agent, and the flavoring agent includes at least one of sucralose, menthol, and passion fruit essence.

9. The method for preparing the pharmaceutical preparation according to any one of claims 5 to 8, characterized in that: The steps include: The pharmaceutical composition and pharmaceutically acceptable excipients are prepared according to the preparation process of pharmaceutical preparations to obtain the pharmaceutical preparation.

10. The method for preparing a pharmaceutical preparation according to claim 9, characterized in that: The pharmaceutical preparation is an oral adhesive tablet, and the preparation process comprises the following steps: Erdosteine, benproperine phosphate, olopatadine hydrochloride, procaterol hydrochloride, a mucosal absorption enhancer, a mucosal adhesion agent, a diluent, a binder, an osmotic pressure enhancer, a glidant, and a lubricant are mixed according to a proportion to obtain a total mixed powder, and the total mixed powder is tableted to obtain a base sheet; A protective layer is formed on one side of the base sheet to obtain an oral adhesive sheet.

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