CN102178658A - Lappaconitine hydrobromide orally disintegrating tablets and preparation method thereof - Google Patents

Abstract

The invention discloses an orally disintegrating tablet of homogenin hydrobromide, which consists of the following components in parts by weight: 5-10 parts of homogenin hydrobromide, 3-10 parts of a disintegrating agent, and a filler 30~100 parts, 2~10 parts of flavoring agent, 0~60 parts of binder, 0~3 parts of lubricant, 0~50 parts of gastric soluble acrylic resin; the prescription does not contain hydrogen bromide of gastric soluble acrylic resin The orally disintegrating tablets of homogenin hydrobromide can be prepared by wet granulation, dry granulation or direct compression; The tablet is made of homogenin hydrobromide into taste-masking granules with gastric-soluble acrylic resin, and then prepared into orally disintegrating tablets by wet granulation tableting method, dry granulation tableting method or direct tableting method; The orally disintegrating tablet of urine hydrobromide not only has a good taste but does not affect the release of the drug, and has a simple preparation process, high yield and low cost, and is suitable for industrial production.

Description

Oral disintegrating tablet of urine hydrobromide and preparation method thereof

technical field

The invention belongs to the field of pharmacy, and relates to an orally disintegrating tablet, in particular to an orally disintegrating tablet of homogenine hydrobromide, and also relates to a preparation method of the orally disintegrating tablet.

Background technique

Aconitum sinomonatum is a diterpene alkaloid extracted from the root of the ranunculaceae plant Aconitum sinomonatum. Its hydrobromide is commonly used in clinical practice. It is the first non-addictive analgesic in my country. Moderate analgesics recommended in the Ministry of Health's "Guiding Principles of Three-Step Pain Relief Therapy for Cancer Patients", suitable for gastrointestinal ulcers, gastritis, hepatitis, cholecystitis, rheumatism, sciatica, toothache, postoperative pain, cancer pain, etc. . Its analgesic effect is equivalent to pethidine, although the onset time is slower, but the drug effect lasts longer. In addition, homogenate hydrobromide also has local anesthesia, cooling, antipyretic and anti-inflammatory effects.

Existing homogenine hydrobromide preparations include injections, patches and ordinary tablets, etc., but due to problems such as inconvenient injections, slow absorption of patches, and slow onset of ordinary tablets, its clinical application is limited. widely used. Therefore, it is of great practical value to develop a homogenine hydrobromide preparation that is easy to carry and use, and has a rapid onset of effect. Orally disintegrating tablet is a new type of tablet that can quickly disintegrate or dissolve in the oral cavity without water. It has the advantages of convenient portability, high patient compliance, and quick onset of action. It is especially suitable for the elderly, children, and those with difficulty swallowing. , Drinking water inconvenience or comatose patients. Therefore, homogenate hydrobromide can be made into orally disintegrating tablets to meet the various needs of clinical treatment. At present, there is no research report on the orally disintegrating tablets of homogenine hydrobromide at home and abroad.

Because the orally disintegrating tablet disintegrates or dissolves in the oral cavity, it has high requirements on the taste, and homogenin hydrobromide tastes bitter and has a numb tongue. Therefore, the problem of taste is homogenin hydrobromide There are technical difficulties in the development of orally disintegrating tablets, otherwise the orally disintegrating tablets are likely to lose the patient's medication compliance due to bad taste, and the treatment plan cannot be carried out smoothly. However, it is not easy to cover up the bitter taste. There are at least 25 kinds of bitter taste receptors in the human mouth. People’s perception threshold for bitter taste is extremely low, and bitter taste lasts longer than sweet and sour tastes, making it difficult to eliminate. Therefore, effectively masking the bitter taste of drugs and improving the quality of preparations is a major challenge for pharmaceutical preparation workers. Although there are many methods for masking bitterness, including spices, sweeteners and amino acids and other flavoring agents; bitterness blockers; cyclodextrin inclusion; microencapsulation; powder coating; drug-ion exchange resin complexes, etc. , but there is not yet a method that is universally applicable to improving bitterness. Moreover, simple taste-masking methods such as adding flavoring agents are often unsatisfactory for taste-masking effects of drugs with strong bitter taste and good water solubility, while taste-masking methods such as cyclodextrin inclusion, microencapsulation, and powder coating have technical limitations. Problems such as complexity, low yield, and easy influence on drug dissolution. Therefore, when developing the orally disintegrating tablets of homogenin hydrobromide, the main problem to be solved is how to make the orally disintegrating tablets have a good taste without affecting the release of the drug, and the preparation process is simple, the yield is high, Low cost and suitable for industrial production.

Contents of the invention

In view of this, the object of the present invention is to provide an orally disintegrating tablet of homogenate hydrobromide, which not only has a good taste but also does not affect the release of the drug, and has a simple preparation process, high yield, low cost, and is suitable for industrialization. Production.

To achieve the above object, the present invention provides the following technical solutions:

1. The orally disintegrating tablet of homogenate hydrobromide consists of the following components in parts by weight: 5-10 parts of homogenine hydrobromide, 3-10 parts of disintegrating agent, 30-100 parts of filler, 2~10 parts of flavoring agent, 0~60 parts of adhesive, 0~3 parts of lubricant, 0~50 parts of stomach-soluble acrylic resin;

The disintegrant is any one or more of croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and citric acid-sodium bicarbonate;

The filler is any one or more of microcrystalline cellulose, lactose, modified starch-1500, mannitol, sorbitol, xylitol, erythrose and powdered sugar;

The flavoring agent is aspartame, stevioside, glycyrrhizin, cyclamate, thaumatin, neotame, citric acid, orange flavor, orange flavor, pineapple flavor, strawberry flavor, chocolate flavor and mint flavor any one or more of

The binder is any one or more of water, ethanol, starch slurry, hydroxypropyl methylcellulose and polyvinylpyrrolidone;

The lubricant is any one or more of magnesium stearate, calcium stearate, micronized silica gel, talcum powder, hydrogenated vegetable oil, polyethylene glycol 6000 and sodium stearate fumarate.

The above technical solutions can be divided into two types according to whether the prescription contains gastric-soluble acrylic resin components: one type is that the prescription does not contain gastric-soluble acrylic resin components, that is, this type of orally disintegrating tablet only uses flavoring The method of masking the bitter taste of homogenin hydrobromide is simple and low cost; the other type is that the prescription contains a gastric-soluble acrylic resin component, that is, this type of orally disintegrating tablet is made of gastric-soluble acrylic resin The method of combining resin with flavoring agent to cover up the bitter taste of homouginine hydrobromide and improve the mouthfeel, mix homouginine hydrobromide with stomach-soluble acrylic resin to make taste-masking granules, because stomach-soluble acrylic resin is in If it does not dissolve in the oral cavity with pH>5, the release of uridine hydrobromide in the oral cavity will be blocked to achieve the effect of masking the taste. The disintegrated particles will be swallowed into the stomach with saliva. Gastric-soluble acrylic resin dissolves quickly, releases homogenine hydrobromide, and acts quickly.

The orally disintegrating tablets of the above first type of urine hydrobromide, preferably, consist of the following components in parts by weight: 5-10 parts of urine hydrobromide, 3-8 parts of a disintegrant , Filling agent 30~70 parts, flavoring agent 5~8 parts, binder 0~50 parts, lubricant 0.5~2 parts. More preferably, it is composed of the following components in parts by weight: 5 parts of quinine hydrobromide, 4.8 parts of cross-linked polyvinylpyrrolidone, 15 parts of microcrystalline cellulose, 30 parts of mannitol, and 5 parts of aspartame , 30 parts of water, 0.5 part of magnesium stearate.

The above-mentioned second type of orally disintegrating tablets of urine hydrobromide, preferably, consists of the following components in parts by weight: 5-10 parts of urine hydrobromide, 3-8 parts of disintegrant , 30-70 parts of filler, 2-5 parts of flavoring agent, 0-50 parts of adhesive, 0.5-2 parts of lubricant, 5-25 parts of stomach-soluble acrylic resin. The stomach-soluble acrylic resin is preferably acrylic resin IV, Eudragit E100 or Eudragit EPO. More preferably, the orally disintegrating tablet of homogenin hydrobromide consists of the following components in parts by weight: 10 parts of homogenin hydrobromide, 8 parts of low-substituted hydroxypropyl cellulose, microcrystalline fiber 20 parts of vegetarian food, 40 parts of xylitol, 4 parts of aspartame, 1 part of talcum powder, 1 part of polyethylene glycol 6000, and 10 parts of Eudragit E100.

2. The preparation method of the orally disintegrating tablet of uricine hydrobromide, according to the different types of prescriptions, its preparation method is respectively as follows:

A． Orally disintegrating tablets of homogenate hydrobromide without gastric-soluble acrylic resin component in the prescription

Orally disintegrating tablets are prepared by wet granulation and tablet compression, dry granulation and tablet compression, preferably wet granulation and tablet compression;

The wet granulation and tabletting method is to mix uginadin hydrobromide, disintegrants, fillers and correctives, pass through a 50-120 mesh sieve, add binders to make soft materials, granulate, 40 Dry at ~60°C until the water content is ≤3%, then add lubricant, mix well, press into tablets, and control the hardness of the tablets to 2~5Kg to get ready;

The dry granulation and tabletting method is to mix homogenine hydrobromide, disintegrating agent, filler and flavoring agent, pass through a 50-120 mesh sieve, dry granulate, pulverize, add lubricant, mix Uniformly, tabletting, control the tablet hardness to 2~5Kg, to get final product;

The direct tableting method is to mix uricine hydrobromide, disintegrating agent, filler, flavoring agent and lubricant, cross a 50-120 mesh sieve, compress tablets, and control the tablet hardness to be 2-5Kg , that is;

B． Orally disintegrating tablets of homogenate hydrobromide containing gastric-soluble acrylic resin component in the prescription

Dissolve the stomach-soluble acrylic resin in a solvent first, then add homogenine hydrobromide under stirring condition, stir evenly, evaporate the solvent, and grind the obtained solid through a 80-150 mesh sieve to obtain taste-masking granules, and then use Orally disintegrating tablets are prepared by wet granulation tableting method, dry granulation tableting method or direct tableting method, preferably using direct tableting method;

The wet granulation and tabletting method is to mix taste-masking granules, disintegrants, fillers and flavoring agents evenly, pass through a 50-120 mesh sieve, add binders to make soft materials, granulate, and dry at 40-60°C When the water content is less than or equal to 3%, granulate, then add a lubricant, mix well, press into tablets, and control the hardness of the tablets to 2~5Kg, that is to say;

The dry granulation and tabletting method is to mix the taste-masking granules, disintegrants, fillers and flavoring agents evenly, pass through a 50-120 mesh sieve, dry granulate, pulverize, add a lubricant, mix well, and tablet , control tablet hardness to be 2 ~ 5Kg, promptly get;

The direct tableting method is to mix taste-masking granules, disintegrants, fillers, flavoring agents and lubricants evenly, pass through a 50-120 mesh sieve, and tablet-press to control the tablet hardness to 2-5Kg.

In the wet granulation tableting method and dry granulation tableting method, the disintegrant can be partially added internally (added before granulation), partially externally added (added after granulation), or all internally or externally added. Binders need to be added in wet granulation and tableting, but not in dry granulation and direct compression. The lubricant can be added as appropriate depending on the fluidity and adhesiveness of the raw materials or particles.

The beneficial effect of the present invention lies in that: the present invention designs the prescription and preparation process of its orally disintegrating tablet according to the physical and chemical properties of homogenin hydrobromide, and finally optimizes a kind of homogenin hydrobromide through a lot of creative work The orally disintegrating tablet has a good taste without affecting the release of the drug, can disintegrate rapidly in the oral cavity, has no irritation to the oral mucosa, can quickly dissolve and take effect in the body, and has a simple preparation process and good reproducibility. The product yield is high, the quality is stable, the requirements for auxiliary materials and equipment are not high, the cost is low, and it is suitable for industrial production. Among them, the orally disintegrating tablet of urine hydrobromide without stomach-soluble acrylic resin component in the prescription has a simpler preparation process, higher yield, lower cost, and faster drug dissolution; while the prescription contains gastric The orally disintegrating tablet of homogenate hydrobromide with soluble acrylic resin component has a better taste-masking effect.

Description of drawings

Figure 1 is a pathological section of the oral mucosa on the administration side of the Oral Disintegrating Tablets of Urine Hydrobromide (100 times magnification), in which A indicates that the structure of the oral mucosa is normal and there is no obvious pathological change, scoring 0; B indicates that Oral mucosal epithelial cell degeneration or flattening, score 1; C, minimal leukocyte infiltration (less than 25 per high-power field), score 1; D, oral mucosal blood vessel hyperemia, score 1; E, oral mucosa Mild blood vessel congestion, score 2 points; F, minimal edema of oral mucosa, score 1 point.

Detailed ways

In order to make the object, technical solution and advantages of the present invention clearer, preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

Embodiment 1. Preparation (wet granulation and tablet compression method) and inspection of orally disintegrating tablets of homogenate hydrobromide without gastric-soluble acrylic resin component in the prescription

Prescription: 5g of homogenate hydrobromide, 4.8g of cross-linked polyvinylpyrrolidone, 15g of microcrystalline cellulose, 30g of mannitol, 5g of aspartame, 30g of water, 0.5g of magnesium stearate, made into 1000 tablets in total .

Preparation process: mix homogenine hydrobromide, cross-linked polyvinylpyrrolidone, microcrystalline cellulose, mannitol and aspartame, pass through a 100-mesh sieve twice, add water to make a soft material, and granulate with a 20-mesh sieve. Dry at 60°C until the water content is less than or equal to 3%, then add magnesium stearate, mix well, and press into tablets to control the hardness of the tablet to 3Kg to obtain the orally disintegrating tablet of urine hydrobromide.

According to the above prescription and preparation process, three batches of orally disintegrating tablets (101, 102, and 103 batches, each batch of 10,000 tablets) were prepared, and the following inspections were carried out:

(1) Inspection of process reproducibility

The preparation results of the three batches of orally disintegrating homogenate hydrobromide tablets are shown in Table 1. It can be seen that the yields of the three batches of homogenine hydrobromide orally disintegrating tablets are stable, indicating that the preparation process has good reproducibility.

Table 1 The preparation results of three batches of orally disintegrating tablets of homogenate hydrobromide

(2) Content uniformity inspection

The content uniformity inspection was carried out according to the second appendix of the Chinese Pharmacopoeia 2010 edition. The results are shown in Table 2. It can be seen that the three batches of orally disintegrating tablets of homogenate hydrobromide are all A+1.80S<15.0, and the content uniformity is qualified.

Table 2 The content uniformity of three batches of orally disintegrating tablets of homogenate hydrobromide

(3) Determination of disintegration time and taste evaluation

The intraoral method of volunteers was adopted: after 6 volunteers rinsed their mouths with water, they took 1 tablet of the sample and placed it on their tongues, and recorded the time of complete disintegration of the sample with a stopwatch, and recorded the volunteer's main complaint of mouthfeel. The results are shown in Table 3. It can be seen that the orally disintegrating tablets of the three batches of homogenate hydrobromide can be disintegrated within 30 seconds, and the taste is good, without bitterness and tongue numbness.

Table 3 Disintegration time and mouthfeel of three batches of orally disintegrating tablets of homogenin hydrobromide

(4) Dissolution determination

Determination by the small cup small pulp method. The accumulative dissolution rates of the commercially available gentine hydrobromide ordinary tablets and the three batches of gentine hydrobromide orally disintegrating tablets are shown in Table 4 and Table 5 respectively. It can be seen that the 10min The dissolution rate was less than 20%, and about 80% was dissolved in 45 minutes; while the orally disintegrating tablet of urine hydrobromide of the present invention was dissolved more than 90% in 2 minutes, and basically dissolved completely in 5 minutes; and the dissolution behavior of the three batches of samples was basically Consistent, further indicating good reproducibility of the preparation process.

Table 4 Cumulative dissolution rate of commercially available urine hydrobromide ordinary tablets

Table 5 Cumulative dissolution rates of three batches of orally disintegrating tablets of homogenate hydrobromide

(5) Stability inspection

101 batches of orally disintegrating tablets of urine hydrobromide were placed in light (4500LUX), high humidity (92.5%RH) or high temperature (60°C) for 10 days respectively, and the properties and disintegration time of the samples before and after placement were investigated , content and changes in related substances. The results are shown in Table 6. It can be seen that the content of the orally disintegrating tablet of uricine hydrobromide of the present invention has decreased under light, high humidity and high temperature conditions, and impurities have increased, but are all within the specified range; wherein, The change under high temperature conditions is more obvious, indicating that the samples are less stable under high temperature conditions. In addition, due to the strong hygroscopicity of the excipients used, the samples absorb more moisture and gain more weight under high humidity conditions, and the disintegration time after moisture absorption is significantly shortened. The ambient temperature and humidity must be strictly controlled during production and transportation, and moisture-proof packaging should be used.

Table 6 Influencing Factors Test of Urine Hydrobromide Orally Disintegrating Tablets

(6) Investigation of oral mucosa irritation

Take 30 golden hamsters and randomly divide them into blank orally disintegrating tablet group, homogenine hydrobromide orally disintegrating tablet (101 batches) low-dose group (5 mg/rat) and high-dose group (10 mg/rat), 10 in each group. The corresponding samples of each group were put in local contact with the cheek pouch of the rat for 4 hours/day, and the drug was administered continuously for 5 days. Finally, the rats in each group were killed by cervical dislocation, and the cheek pouch on the side (right side) of each rat and the control group were removed. The side (left side) cheek pouch was placed in formalin solution with a volume fraction of 10% and collected according to conventional methods, prepared in paraffin, stained with HE, mounted in gum, and observed with OLYMPUSBX51 biological microscope and pathological tissue image analysis system And ingest images, according to the "Pathological Reaction Scoring Criteria of Oral Mucosa" and "Pathological Reaction Grading", grade the pathological reaction of the oral mucosa of the control side and the administration side of each animal, and carry out according to the grading of the pathological reaction of the oral mucosa of each group of animals Drug irritation evaluation.

Result: A. General examination: There were no obvious abnormalities in the size, shape, color and texture of the cheek pouches of the rats in each group.

B． Histological examination: See Figure 1 for the pathological section of the oral mucosa on the administration side of the Oral Disintegrating Tablets, see Table 7, see Both the high-dose and low-dose groups of orally disintegrating gluconate hydrobromide tablets had no irritation to the oral mucosa of golden hamsters.

Table 7 Score of pathological response to oral mucosal irritation of orally-disintegrating gluconate hydrobromide tablets

Embodiment 2. Preparation of orally disintegrating tablets of homogenate hydrobromide without gastric-soluble acrylic resin component in the prescription (dry granulation and tablet compression method)

Prescription: 10g of homogenate hydrobromide, 5g of cross-linked polyvinylpyrrolidone, 40g of modified starch-1500, 30g of sorbitol, 2g of glycyrrhizin, 5g of thaumatin, 1g of mint essence, 1g of magnesium stearate, talc Powder 1g, made into 1000 tablets in total.

Preparation process: mix homogenate hydrobromide, cross-linked polyvinylpyrrolidone, modified starch-1500, sorbitol, glycyrrhizin, thaumatin and mint essence, pass through a 120-mesh sieve for 3 times, and dry granulate , pulverized, crossed 20 mesh sieves, then added magnesium stearate and talcum powder, mixed evenly, compressed into tablets, and the tablet hardness was controlled to be 5Kg, to obtain the orally disintegrating tablets of uricine hydrobromide.

Similar to the orally disintegrating tablet obtained in Example 1, the orally disintegrating tablet of homogenate hydrobromide prepared in this example disintegrates rapidly within 1 min in the oral cavity, and basically dissolves completely in 5 min in water. Non-irritating, good taste, no obvious bitterness and tongue numbness, with a cool feeling of mint. The dry granulation and tabletting method does not contact with heat and humidity, and the drug is relatively stable during the preparation process. However, for pharmaceutical factories without a dry granulator, the production cost will increase to a certain extent due to the need to purchase a dry granulator.

Embodiment 3. Preparation of orally disintegrating tablets of homogenate hydrobromide without gastric-soluble acrylic resin component in the prescription (direct compression method)

Prescription: 5g of urine hydrobromide, 3g of croscarmellose sodium, 15g of microcrystalline cellulose, 15g of sorbitol, 2g of glycyrrhizin, 2g of aspartame, 1g of citric acid, 1g of orange essence, Magnesium stearate 0.5g, made into 1000 tablets in total.

Preparation process: mix homogenate hydrobromide, croscarmellose sodium, microcrystalline cellulose, sorbitol, glycyrrhizin, aspartame and chocolate essence, pass through 80-mesh sieve for 3 times, Then add magnesium stearate, mix evenly, and press into tablets to control the hardness of the tablet to 4Kg to obtain the orally disintegrating tablet of uricine hydrobromide.

Similar to the orally disintegrating tablet obtained in Example 1, the orally disintegrating tablet of homogenate hydrobromide prepared in this example disintegrates rapidly within 1 min in the oral cavity, and basically dissolves completely in 5 min in water. Non-irritating, sweet and sour taste, no obvious bitterness and tongue numbness, with orange taste. The direct compression method is simpler than the granulation and tableting method, but the fluidity of the powder is slightly poorer, so the requirements for the tableting machine are higher.

Embodiment 4. Preparation (direct compression method) and inspection of orally disintegrating tablets of homogenate hydrobromide containing stomach-dissolving acrylic resin component in the prescription

Prescription: 10g of urinadin hydrobromide, 8g of low-substituted hydroxypropyl cellulose, 20g of microcrystalline cellulose, 40g of xylitol, 4g of aspartame, 1g of talcum powder, 1g of polyethylene glycol 6000, Eudragit E100 10g, made into 1000 pieces in total.

Preparation process: after dissolving Eudragit E100 in ethanol, add homouginine hydrobromide under high-speed stirring condition, stir evenly, evaporate the solvent, and grind the obtained solid through an 80-mesh sieve to obtain taste-masking granules, then add low-substituted Mix hydroxypropyl cellulose, microcrystalline cellulose, xylitol, aspartame, talcum powder and polyethylene glycol, pass through an 80-mesh sieve for 3 times, and press into tablets to control the hardness of the tablet to 2.5Kg, to obtain Oral disintegrating tablets of uricine hydrobromide.

According to the above prescription and preparation process, three batches of orally disintegrating tablets of uricine hydrobromide (batches 201, 202, and 203, each batch of 10,000 tablets) were prepared, and the following inspections were carried out:

(1) Inspection of process reproducibility

The preparation results of the three batches of orally disintegrating homogenin hydrobromide tablets are shown in Table 8. It can be seen that the yields of the three batches of homogenin hydrobromide orally disintegrating tablets are stable, indicating good reproducibility of the preparation process.

Table 8 The preparation results of three batches of orally disintegrating tablets of homogenate hydrobromide

(2) Content uniformity inspection

The content uniformity inspection was carried out according to the second appendix of the Chinese Pharmacopoeia 2010 edition. The results are shown in Table 9. It can be seen that the three batches of orally disintegrating tablets of homogenate hydrobromide are all A+1.80S<15.0, and the content uniformity is qualified.

Table 9 Content Uniformity of Three Batches of Urine Hydrobromide Orally Disintegrating Tablets

(3) Determination of disintegration time and taste evaluation

Intraoral method of volunteers was used for determination: after 6 volunteers rinsed their mouths with water, they took 1 tablet of the sample and placed it on their tongues, and recorded the time of complete disintegration of the sample with a stopwatch, and at the same time recorded the mouthfeel of the volunteers. The results are shown in Table 10. It can be seen that the orally disintegrating tablets of the three batches of homogenate hydrobromide can be disintegrated within 30 seconds, and the taste is good, without bitterness and tongue numbness.

Table 10 Disintegration time and mouthfeel of three batches of orally disintegrating tablets of homogenate hydrobromide

(4) Dissolution determination

Determination by the small cup small pulp method. The accumulative dissolution rates of the commercially available urine hydrobromide ordinary tablets and three batches of urine hydrobromide orally disintegrating tablets are shown in Table 4 and Table 11 respectively. It can be seen that the 10min The dissolution rate was less than 20%, and about 80% was dissolved in 45 minutes; while the orally disintegrating tablet of urine hydrobromide of the present invention was dissolved more than 90% in 2 minutes, and basically dissolved completely in 5 minutes; and the dissolution behavior of the three batches of samples was basically Consistent, further indicating good reproducibility of the preparation process.

Table 11 Cumulative dissolution rate of three batches of orally disintegrating tablets of homogenate hydrobromide

(5) Stability inspection

201 batches of orally disintegrating tablets of uricine hydrobromide were placed in light (4500LUX), high humidity (92.5%RH) or high temperature (60°C) for 10 days respectively, and the properties and disintegration time of the samples before and after placement were investigated , content and changes in related substances. The results are shown in Table 12. It can be seen that the content of the orally disintegrating tablet of uricine hydrobromide of the present invention has decreased under light, high humidity and high temperature conditions, and impurities have increased, but are all within the specified range; wherein, The change under high temperature conditions is more obvious, indicating that the samples are less stable under high temperature conditions. In addition, due to the strong hygroscopicity of the excipients used, the samples absorb more moisture and gain more weight under high humidity conditions, and the disintegration time after moisture absorption is significantly shortened. The ambient temperature and humidity must be strictly controlled during production and transportation, and moisture-proof packaging should be used.

Table 12 Influencing factor test of homogenate hydrobromide orally disintegrating tablets

(6) Investigation of oral mucosa irritation

Take 30 golden hamsters and randomly divide them into blank orally disintegrating tablet group, homogenine hydrobromide orally disintegrating tablet (201 batches) low-dose group (5 mg/rat) and high-dose group (10 mg/rat), 10 in each group. The corresponding samples of each group were put in local contact with the cheek pouch of the rat for 4 hours/day, and the drug was administered continuously for 5 days. (Left side) cheek pouch, placed in formalin solution with a volume fraction of 10% and collected according to conventional methods, prepared in paraffin, stained with HE, mounted in gum, observed and analyzed with OLYMPUSBX51 biological microscope and pathological tissue image analysis system Take the images, and grade the pathological reactions of the oral mucosa of the control side and administration side of each animal according to the "Pathological Reaction Scoring Criteria of Oral Mucosa Histopathology" and "Grading of Pathological Reaction" Stimulus evaluation. The results showed that there were no obvious abnormalities in the size, shape, color and texture of the cheek pouches of the rats in each group; the high-dose and low-dose groups of the orally disintegrating tablets of homogenate hydrobromide had no irritation to the oral mucosa of golden hamsters .

Comparing Example 1 with Example 4, it can be seen that the orally disintegrating tablets of homogenate hydrobromide that do not contain gastric-soluble acrylic resin components in the prescription are simpler in preparation process, higher in yield, and cheaper in cost. The drug dissolves faster; while the orally disintegrating tablet of urinadin hydrobromide containing a gastric-soluble acrylic resin component in the prescription has a better taste-masking effect. Because the fluidity of the powder is poor when it is directly compressed into tablets, the preparation method of the orally disintegrating tablets of homogenate hydrobromide that does not contain a gastric-soluble acrylic resin component in the prescription is preferably the wet granulation tableting method; while the prescription contains The orally disintegrating tablets of homogenate hydrobromide with a stomach-soluble acrylic resin component are made into taste-masking granules first and then compressed into tablets. The fluidity of the granules is better than that of powders, so the preparation method is preferably the direct compression method.

Embodiment 5. Preparation of Orally Disintegrating Tablets Containing Gastric-soluble Acrylic Resin Component in the Prescription (Dry Granulation and Tablet Compression)

Prescription: 5g homogenate hydrobromide, 4g sodium carboxymethyl starch, 20g microcrystalline cellulose, 15g erythrose, 2g glycyrrhizin, 1g aspartame, 1g chocolate essence, 1g micronized silica gel, Fuma Sodium stearate 1g, acrylic resin IV 15g, made into 1000 tablets in total.

Preparation process: after dissolving acrylic resin IV with ethanol, add homougina hydrobromide under high-speed stirring condition, stir evenly, evaporate the solvent, and crush the obtained solid through a 120-mesh sieve to obtain taste-masking granules, then add carboxylate Mix methyl starch sodium, microcrystalline cellulose, erythrose, glycyrrhizin, aspartame and chocolate essence, pass through 80 mesh sieve for 3 times, dry granulate, crush, pass through 20 mesh sieve, then add micropowder silica gel And sodium stearate fumarate, mix, tabletting, control tablet hardness to be 5Kg, obtain the orally disintegrating tablet of uricine hydrobromide.

Similar to the orally disintegrating tablet obtained in Example 4, the orally disintegrating tablet of homogenate hydrobromide prepared in this example disintegrates rapidly within 1 min in the oral cavity, and basically dissolves completely in 5 min in water. Non-irritating, cool and sweet taste, no bitterness and tongue numbness, but slightly gritty.

Embodiment 6. Preparation of Orally Disintegrating Tablets Containing Gastric-soluble Acrylic Resin Component in the Prescription (Wet Granulation Tablet Compression Method)

Prescription: 10g of homogenin hydrobromide, 6g of low-substituted hydroxypropyl cellulose, 30g of lactose, 30g of mannitol, 2g of stevioside, 50g of starch slurry with a mass fraction of 5%, 1g of micropowdered silica gel, polyethylene glycol 6000 1g, Eudragit EPO 25g, made into 1000 tablets in total.

Preparation process: after dissolving Eudragit EPO in ethanol, add homougine hydrobromide under high-speed stirring condition, stir evenly, evaporate the solvent, and crush the obtained solid through a 100-mesh sieve to obtain taste-masking granules, then add low-substituted Mix hydroxypropyl cellulose, lactose, mannitol and stevioside, pass through a 50-mesh sieve three times, add starch slurry with a mass fraction of 5% to make a soft material, granulate with a 20-mesh sieve, and dry at 40°C until the water content is ≤3% , then add micropowdered silica gel and polyethylene glycol 6000, mix evenly, and press into tablets to control the hardness of the tablet to 3Kg to obtain the orally disintegrating tablet of uricine hydrobromide.

Similar to the orally disintegrating tablet obtained in Example 4, the orally disintegrating tablet of homogenate hydrobromide prepared in this example disintegrates rapidly within 1 min in the oral cavity, and basically dissolves completely in 5 min in water. Non-irritating, good taste, no bitterness and tongue numbness, but the gritty feeling is more obvious.

Finally, it is noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described with reference to the preferred embodiments of the present invention, those skilled in the art should understand that it can be described in the form Various changes may be made in matter and details thereof without departing from the spirit and scope of the invention as defined in the appended claims.

Claims (7)

1. The orally disintegrating tablet of homogenin hydrobromide is characterized in that: it consists of the following components in parts by weight: 5-10 parts of homogenin hydrobromide, 3-10 parts of disintegrant, filler 30~100 parts, 2~10 parts of flavoring agent, 0~60 parts of adhesive, 0~3 parts of lubricant, 0~50 parts of stomach-soluble acrylic resin; The disintegrant is any one or more of croscarmellose sodium, crospovidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose; The filler is any one or more of microcrystalline cellulose, lactose, modified starch-1500, mannitol, sorbitol, xylitol and erythrose; The flavoring agent is aspartame, stevioside, glycyrrhizin, cyclamate, thaumatin, neotame, citric acid, orange flavor, orange flavor, pineapple flavor, strawberry flavor, chocolate flavor and mint flavor any one or more of The binder is any one or more of water, ethanol, starch slurry, hydroxypropyl methylcellulose and polyvinylpyrrolidone; The lubricant is any one or more of magnesium stearate, calcium stearate, micronized silica gel, talcum powder, polyethylene glycol 6000 and sodium stearate fumarate. 2. The orally disintegrating tablet of quinine hydrobromide according to claim 1, characterized in that: it is composed of the following components in parts by weight: 5-10 parts of quinine hydrobromide, disintegrant 3-8 parts, filler 30-70 parts, flavoring agent 5-8 parts, binder 0-50 parts, lubricant 0.5-2 parts. 3. The orally disintegrating tablet of quinine hydrobromide according to claim 2, characterized in that: it is composed of the following components in parts by weight: 5 parts of quinine hydrobromide, cross-linked polyvinylpyrrolidone 4.8 parts, microcrystalline cellulose 15 parts, mannitol 30 parts, aspartame 5 parts, water 30 parts, magnesium stearate 0.5 parts. 4. The orally disintegrating tablet of quinine hydrobromide according to claim 1, characterized in that: it consists of the following components in parts by weight: 5-10 parts of quinine hydrobromide, disintegrant 3-8 parts, filler 30-70 parts, flavoring agent 2-5 parts, binder 0-50 parts, lubricant 0.5-2 parts, stomach-soluble acrylic resin 5-25 parts. 5. The orally disintegrating tablet of homouginine hydrobromide according to claim 1 or 4, characterized in that: the stomach-soluble acrylic resin is acrylic resin IV, Eudragit E100 or Eudragit EPO. 6. The orally disintegrating tablet of quinine hydrobromide according to claim 5, characterized in that: it consists of the following components in parts by weight: 10 parts of quinine hydrobromide, low-substituted hydroxypropyl 8 parts of cellulose, 20 parts of microcrystalline cellulose, 40 parts of xylitol, 4 parts of aspartame, 1 part of talc, 1 part of polyethylene glycol 6000, and 10 parts of Eudragit E100. 7. the preparation method of the described homogenate hydrobromide orally disintegrating tablet of claim 1, is characterized in that: A． Orally disintegrating tablets of homogenate hydrobromide that do not contain gastric-soluble acrylic resin components in the prescription Orally disintegrating tablets are prepared by wet granulation tableting method, dry granulation tableting method or direct tableting method; The wet granulation and tabletting method is to mix homogenine hydrobromide, fillers and flavoring agents, pass through a 50-120 mesh sieve, add binders to make soft materials, granulate, and dry at 40-60°C When the water content is less than or equal to 3%, add a lubricant, mix well, and press into tablets to control the hardness of the tablets to 2-5Kg. The dry granulation and tabletting method is to mix homogenine hydrobromide, disintegrating agent, filler and flavoring agent, pass through a 50-120 mesh sieve, dry granulate, pulverize, add lubricant, mix Uniformly, tabletting, control the tablet hardness to 2~5Kg, to get final product; The direct tableting method is to mix uricine hydrobromide, disintegrating agent, filler, flavoring agent and lubricant, cross a 50-120 mesh sieve, compress tablets, and control the tablet hardness to be 2-5Kg , that is; B． Orally disintegrating tablets of homogenate hydrobromide containing gastric-soluble acrylic resin component in the prescription Dissolve the stomach-soluble acrylic resin in a solvent first, then add homogenine hydrobromide under stirring condition, stir evenly, evaporate the solvent, and grind the obtained solid through a 80-150 mesh sieve to obtain taste-masking granules, and then use Preparation of orally disintegrating tablets by wet granulation tableting method, dry granulation tableting method or direct tableting method; The wet granulation and tabletting method is to mix taste-masking granules, disintegrants, fillers and flavoring agents evenly, pass through a 50-120 mesh sieve, add binders to make soft materials, granulate, and dry at 40-60°C When the water content is less than or equal to 3%, granulate, then add a lubricant, mix well, press into tablets, and control the hardness of the tablets to 2~5Kg, that is to say; The dry granulation and tabletting method is to mix the taste-masking granules, disintegrants, fillers and flavoring agents evenly, pass through a 50-120 mesh sieve, dry granulate, pulverize, add a lubricant, mix well, and tablet , control tablet hardness to be 2 ~ 5Kg, promptly get; The direct tableting method is to mix taste-masking granules, disintegrants, fillers, flavoring agents and lubricants evenly, pass through a 50-120 mesh sieve, and tablet-press to control the tablet hardness to 2-5Kg.

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