CN1270721C - Rapid disintegration and rapid dissolution tablet containing kakonein - Google Patents

Abstract

The invention belongs to the field of pharmaceutical preparations, and relates to a rapidly disintegrating and rapidly dissolving tablet containing the active ingredient puerarin. The invention combines the active ingredient puerarin with a disintegrating agent, a filler, a flavoring agent, a lubricant, an effervescent agent, The binder and the coloring agent are mixed to make a fast disintegrating tablet through a pressing process. Each tablet of the preparation of the invention contains 10-100 mg of puerarin, the dosage of the disintegrating agent accounts for 2-20% of the total weight of the tablet, and the contained solubilizer accounts for 1-10% of the total weight of the tablet. The tablet of the present invention disintegrates in less than 1 minute in contact with saliva in the oral cavity, and dissolves more than 80% of the total amount in 3 minutes, and has the advantages of rapid disintegration, convenient use and fast dissolution rate.

Description

Rapidly Disintegrating Fast Dissolving Tablets Containing Puerarin

technical field

The invention belongs to the field of pharmaceutical preparations and relates to a rapidly disintegrating and rapidly dissolving tablet, in particular to a rapidly disintegrating and rapidly dissolving tablet containing puerarin as an active ingredient.

Background technique

Orally fast-disintegrating tablet (orally rapidly-disintegrating tablet, ororally rapidly-disintegrating tablet) is a new pharmaceutical preparation that has emerged at home and abroad in the past ten years. features. Orally rapidly disintegrating tablets can be administered without water and with only a small amount of saliva. Generally speaking, orally rapidly disintegrating tablets should disintegrate within 1 minute after contacting saliva in the oral cavity. After disintegration, the drug is rapidly dissolved or dispersed into small particles, which speeds up the absorption and makes the onset of effect rapid. This dosage form is suitable for: (1) patients with swallowing difficulties such as children and elderly patients; (2) patients with digestive tract diseases who cannot swallow or swallowing actions cause severe vomiting reactions; (3) bedridden patients or people who are busy at work or travel or, especially when water is not available; (4) when the drug needs to take effect quickly. Certain diseases such as cardiovascular disease, asthma, allergies, pain, etc. require rapid administration.

Orally rapidly disintegrating tablets are mainly prepared by freeze-drying and compression methods. Orally disintegrating tablet technology (Zydis) prepared by freeze-drying method is to make a solution or suspension of the active ingredient of the drug and various excipients or additives, inject it into a mold of a certain shape, freeze it into a solid quickly, and then reduce the pressure to sublimate the water. In this way, a tablet with a porous structure is formed. This kind of tablet has a loose structure and is rich in small voids, which can quickly absorb water and dissolve. Generally, the disintegration time in the oral cavity can reach within 10 seconds. At present, drugs that are made into orally rapidly disintegrating tablets using this technology mainly include: oxazepam, lorazepam, piroxicam, loperamide, famotidine, loratadine, enalapril , phenylpropanolamine/brompheniramine, ondansetron, rizatriptan benzoate (Rizatriptan Benzoate), domperidone, nitroglycerin, isosorbide dinitrate, nifedipine, difenidol hydrochloride, hydrochloride Meclizine and others (J PharmPharmacol, 1998, 50: 375; PLA Pharmaceutical Journal, 2000, 16: 206). However, this method requires special freeze-drying equipment, the process is complex, the cost is high, and the obtained tablet has poor mechanical strength. Orally rapidly disintegrating tablets prepared by compression method have small porosity and slightly slower disintegration. However, the preparation process is simple and the mechanical strength is good. At present, the medicines made into orally rapidly disintegrating tablets mainly include zomitriptan, minazepril, baclofen, carbidopa/levodopa, carisprodol and the like.

It has been reported that the disintegration time of rapidly disintegrating tablets prepared by compression method is mainly determined by the selected disintegrant. Croscarmellose sodium, crospovidone, etc. with excellent disintegration properties are often used (Foreign Medicine and Pharmacy, 1998, 25: 293). The amount of filler and disintegrant has an important influence on the disintegration time, and the amount of disintegrant can reach more than 15% of the tablet weight. Lactose, mannitol, microcrystalline cellulose, etc. are commonly used as fillers. For medicines with a bitter taste, the powder coating method can be used to cover the taste of the medicine, and then be compressed into orally rapidly disintegrating tablets (CN1328446A).

For drugs that are easily soluble in water, after being made into fast-disintegrating tablets, the dissolution of the drug is very rapid because the dissolution is a non-rate-limiting process, so that the drug starts to be absorbed in the oral cavity and has a rapid onset of action. For insoluble drugs in water, since the dissolution is the rate-limiting process, although the fast-disintegrating tablets made can disintegrate rapidly, the drug exists in the original crystal form after the disintegration of the tablet, and it still needs a process to be absorbed after dissolution. So the onset is slower. Most of the orally rapidly disintegrating tablets reported so far contain water-soluble drugs. The preparation of orally rapidly disintegrating tablets from insoluble drugs has the following difficulties: (1) the drug itself is hydrophobic, which affects the disintegration of the tablet; (2) the drug is in a suspended state after the disintegration of the tablet, and the onset of action is slow.

Puerarin is a monomer-isoflavone compound extracted from the dried root of Pueraria mirifica, which has been widely used in the treatment of cardiovascular and cerebrovascular diseases and other diseases. The main indications include coronary heart disease, ischemic cerebrovascular disease, diabetes complicated by microangiopathy, peripheral arterial ischemic disease, sudden deafness, etc. Most of the patients are elderly people, who are often accompanied by inconvenience in mobility due to the influence of cardiovascular and cerebrovascular diseases. Puerarin is a water-insoluble drug. The oral dosage form currently used clinically is sugar-coated tablet. The in vitro disintegration time is 30-60 minutes, and the dissolution rate is less than 10% in 2 hours. The drug dissolves slowly and absorbs slowly, so the onset of action is slow, and it is difficult to guarantee the curative effect due to incomplete absorption.

Contents of the invention

The object of the present invention is to provide an orally rapidly disintegrating and fast-dissolving tablet containing the active ingredient puerarin, so as to facilitate administration and accelerate dissolution to accelerate absorption. More precisely, the rapidly disintegrating and rapidly dissolving tablet involved in the present invention is a tablet that can disintegrate rapidly within 1 minute of contact with saliva in the oral cavity, and dissolve more than 80% of the total amount in 3 minutes. A convenient oral pharmaceutical formulation.

The rapidly disintegrating and rapidly dissolving tablet of the present invention uses puerarin as an active ingredient, and also contains a mixture of excipients including a strong disintegrating agent and a strong solubilizing agent.

The tablet of the present invention is prepared by a compression method. In order to achieve the effect of disintegrating with saliva in the oral cavity, the optimal formula is adopted in pharmacy technology so that it can be disintegrated rapidly within less than 1 minute of contact with saliva in the oral cavity. Preferably less than 30 seconds. The invention has the advantages of disintegrating the tablet only through the action of saliva without drinking water when taking it and adding a solubilizing agent to accelerate the dissolution.

The weight ratio of the active ingredient puerarin in the tablet of the present invention to the excipient is 1:1-1:50, preferably 1:5-1:10.

The mixture of excipients of the described strong disintegrant and strong solubilizer includes filler, disintegrator, solubilizer, sweetener, binding agent, lubricant, coloring agent and/or effervescent agent The mixture of excipients plays the roles of maintaining tablet weight, tablet shape, disintegration, solubilizing, binding, coloring, wetting and flavoring respectively.

Wherein the filler is 40%-90% of the total weight of the tablet, preferably 60-80%. Microcrystalline cellulose, mannitol, lactose, xylitol, sucrose, glucose, starch, pregelatinized starch, calcium sulfate, calcium carbonate, calcium phosphate, light magnesium oxide and mixtures thereof can be selected, among which microcrystalline cellulose is preferred , lactose and mannitol. The tablet of the invention has smooth appearance and good compressibility, and the tablet can reach suitable hardness. The mannitol absorbs heat when dissolved and has a sweet taste, so it has a cool and refreshing feeling in the oral cavity. The microcrystalline cellulose also functions as a filler, a disintegrant, a binder, and a lubricant, and can improve the compressibility of the tablet powder.

The tablet of the present invention contains a disintegrant, and its dosage is 2% to 20% of the total weight of the tablet, preferably 5% to 15%. The disintegrant can be selected from crospovidone, croscarmellose sodium, carboxymethyl starch sodium, hydroxypropyl starch, low-substituted hydroxypropyl cellulose and their mixtures, which can swell rapidly after meeting water , so that the tablet disintegrates quickly. The disintegration time of the tablet decreased with the increase of the disintegrant dosage. The disintegrating agent can be added by internal addition, external addition and internal and external addition.

The tablet of the present invention may also contain an effervescent agent as a driving force for disintegration. Its dosage accounts for 0%-40% of the total weight of the tablet, preferably 1%-10%.

The effervescent agent consists of organic acid and base. Wherein the organic acid may be citric acid, tartaric acid, succinic acid, lactic acid, glycolic acid, oxalic acid, gluconic acid, citric anhydride, succinic anhydride, tartaric anhydride and mixtures thereof. Wherein the base may be sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, calcium bicarbonate, magnesium carbonate, barium carbonate and mixtures thereof.

The puerarin in the tablet of the present invention is a poorly soluble drug, and the problem of dissolution often exists when it is taken orally in solid form, so a solubilizing agent or a cosolvent is added to the tablet of the present invention to increase the dissolution. Its dosage is 1%-20% of the total weight of the tablet, preferably 3%-10%. The solubilizer may include poloxamer (polyoxyethylene-polyoxypropylene copolymer), Tweens, Spans, sodium lauryl sulfate, sodium cetyl sulfate, sodium octadecyl sulfate , Sodium Dioctylsuccinate Sulfonate, Sodium Dihexylsuccinate Sulfonate, Sodium Dodecyl Sulfonate, Sodium Dodecylbenzene Sulfonate, Sodium Glycocholate, Sodium Taurocholate, β-Cyclopaste Alcohol and hydroxypropyl beta-cyclodextrin. The co-solvents include nicotinamide, benzoic acid, sodium benzoate and mixtures thereof. Solubilizers or co-solvents can increase the wetting of puerarin, accelerate the dissolution rate, and ensure the efficacy of the drug. The tablet of the present invention is tested in an intelligent drug dissolution apparatus (Tianjin University Radio Factory) according to the dissolution test method (two appendices of "Pharmacopoeia of the People's Republic of China" 2000 edition), and the dissolution rate in 3 minutes is not less than 80%.

The excipients of the tablet of the present invention may contain binders or wetting agents. Especially selected from starch paste, povidone paste, hypromellose paste, methylcellulose (sodium) paste, carboxymethylcellulose (sodium) paste, water, ethanol and mixtures thereof. The type, amount and usage of the binder have a great influence on the disintegration performance and dissolution of the tablet. It can be a dry filler with adhesive properties, which is suitable for preparing tablets by direct compression technology, or it can be a liquid glue or solution, which has adhesive or wetting effects.

The excipients of the tablet of the present invention may contain sweeteners and optionally coloring agents, flavoring agents, lubricants.

The sweetener is especially selected from aspartame, acesulfame potassium, sodium saccharin, neohesperidin dihydrochalcone and mixtures thereof. The dosage is 1% to 10% of the total weight of the tablet, preferably 2% to 5%.

The tablet of the present invention has a suitable hardness, usually between 20 and 70 Newtons, and can withstand various treatments under normal operating conditions without greatly affecting its properties.

The tablet of the present invention can be prepared by the following method or other pharmaceutically appropriate methods. First, the active ingredient puerarin and various excipients are crushed through an 80-mesh sieve, and after precise weighing according to the formula amount, the puerarin is evenly mixed with fillers, disintegrants, solubilizers, sweeteners, and colorants. Add appropriate amount of binder or wetting agent to make wet granules, dry at a certain temperature to obtain dry granules, add lubricant, and press to form.

Detailed ways

Example 1 Rapid Disintegration and Rapid Dissolution Tablets Containing Puerarin Using Microcrystalline Cellulose as Filler

Tablets are prepared according to the following composition ratio. Raw materials and accessories Recipe 1 Recipe 2 Recipe 3 Puerarin 50.00mg 50.00mg 50.00mg microcrystalline cellulose 65.61 mg 44.39mg 70.00mg lactose 150.00mg 150.00mg 150.00mg Crospovidone 44.14mg 25.86mg 40mg aspartame 8.00mg 8.00mg 8.00mg

Ester citric acid 5.00mg 5.00mg 5.00mg sodium bicarbonate 6.00mg 6.00mg 6.00mg Poloxamer 2.00mg 2.00mg 2.00mg Iron oxide (red) 0.001% 0.001% 0.001% 5% starch slurry Regular amount Regular amount Regular amount Magnesium stearate 1% 1% 1%

Prepare as follows.

Pass the active ingredient puerarin in the formula and the listed excipients through 80-mesh sieve respectively.

Mix puerarin, microcrystalline cellulose, lactose, crospovidone, aspartame, poloxamer, citric acid, and sodium bicarbonate evenly.

Add 5% starch slurry to make soft material, extrude and sieve through a 20-mesh sieve to granulate.

The wet granules were dried at a constant temperature of 60°C for 2 hours.

The dry granules are sieved with a 20-mesh sieve.

Add magnesium stearate and mix well.

It is compressed on a tablet machine, with an average tablet weight of 300mg~350mg, and a tensile strength of 20~50 Newtons.

The disintegration time limit of orally disintegrating tablets was checked by the method reported in the literature (Powder Technology, 2002, 122:188~~198). The dissolution test method is carried out according to the first method of the dissolution test method in the second appendix XC of the "Pharmacopoeia of the People's Republic of China" in 2000, and its 3-minute dissolution rate is greater than 80%.

Table 1 is the test results of the disintegration time limit of the puerarin orally disintegrating tablets in Example 1. Table 2 is the investigation result of the dissolution rate (%) of the puerarin orally rapidly disintegrating fast-dissolving tablets.

Table 1 Recipe 1 (seconds) Recipe 2 (seconds) Recipe 3 (seconds) 1 32 twenty four 20 2 twenty three 27 twenty three 3 twenty two 30 20 4 28 34 27 5 25 twenty four twenty three 6 29 40 twenty one X±SD 26.50±3.83 29.83±1.83 22.33±2.66

Table 2 time (minutes) cup number X±SD 1 2 3 3 82.35 82.78 83.16 82.76±0.41 5 91.34 88.87 87.55 89.25±1.92 15 95.77 92.49 91.82 93.36±2.11 45 94.85 92.46 91.52 92.94±1.72

Embodiment 2: Puerarin orally rapidly disintegrating tablet containing mannitol as a filler

Tablets are prepared according to the following composition ratio, and the dose of puerarin is 25-75 mg. Raw materials and accessories Recipe.4 Recipe 5 Recipe 6 Puerarin 25.00mg 50.00mg 75.00mg Mannitol 110.00mg 170.00mg 200.00mg Crospovidone 25.00mg 40.00mg 60.00mg Aspartame 8.00mg 8.00mg 8.00mg citric acid 5.00mg 5.00mg 5.00mg sodium bicarbonate 6.00mg 6.00mg 6.00mg Poloxamer 2.00mg 2.00mg 2.00mg Iron oxide (red) 0.001% 0.001% 0.001% 5% starch slurry Conventional amount Conventional amount Conventional amount Magnesium stearate 1% 1% 1%

The preparation steps are the same as in Example 1.

Compressed on a tablet machine, the average tablet weight is between .190mg and 370mg, and the tensile strength is between 20 and 50 Newtons. Since mannitol absorbs heat when dissolving, it has a cooling sensation when it disintegrates in the mouth, which helps to improve the taste of the tablet.

The disintegration time limit and dissolution test method are the same as in Example 1.

Table 3 is the test results of the disintegration time limit and dissolution rate of the puerarin orally disintegrating tablets in Example 2.

table 3 Recipe 4 Recipe 5 Recipe 6 Disintegration time (seconds) 18.48±3.37 26.89±2.66 30.12±4.62 3 minutes dissolution rate >80% >80% >80%

Embodiment 3: Puerarin orally disintegrating tablet containing carbohydrates and starches.

Tablets are prepared according to the following composition ratio. Raw materials and accessories Recipe.7 Recipe 8 Recipe 9 Puerarin 50.00mg 50.00mg 50.00mg glucose 50.00mg 25.00mg 75.00mg pregelatinized starch 50.00mg 75.00mg 25.00mg Sodium carboxymethyl starch 40.00mg 40mg 40mg Aspartame 8.00mg 8.00mg 8.00mg citric acid 5.00mg 5.00mg 5.00mg sodium bicarbonate 6.00mg 6.00mg 6.00mg Poloxamer 2.00mg 2.00mg 2.00mg Iron oxide (red) 0.001% 0.001% 0.001% 5% starch slurry Conventional amount Conventional amount Conventional amount Magnesium stearate 1% 1% 1%

The preparation steps are the same as in Example 1. Sugar and starch are used as fillers and disintegrants, which are low in price.

It is pressed on a tablet press, with an average tablet weight of about 230mg and a tensile strength of 20-50 Newtons.

The disintegration time limit and dissolution test method are the same as in Example 1.

Table 4 shows the disintegration time limit and dissolution test results of the puerarin orally disintegrating tablets in Example 3.

Table 4 Recipe 7 Recipe 8 Recipe 9 Disintegration time (seconds) 35.25±1.65 43.79±2.08 27.68±3.92 3 minutes dissolution rate >80% >80% >80%

Example 4: Puerarin orally disintegrating tablet containing low-substituted hydroxypropyl cellulose.

Tablets are prepared according to the following composition ratio. Raw materials and accessories Recipe 10 Puerarin 50.00mg microcrystalline cellulose 70.00mg Low-substituted hydroxypropyl fiber 150.00mg

white Sodium Saccharin 10.00mg tartaric acid 5.00mg magnesium carbonate 6.00mg Poloxamer 2.00mg Iron oxide (red) 0.001% 5% starch slurry Regular amount Magnesium stearate 1%

The preparation steps are the same as in Example 1.

It is pressed on a tablet press, with an average tablet weight of about 300mg and a tensile strength of 20-50 Newtons.

The disintegration time limit and dissolution test method are the same as in Example 1. The disintegration time is about 32.37±3.35 seconds, and the dissolution rate is greater than 80% in 3 minutes.

Example 5: Puerarin orally disintegrating tablet containing surfactant.

Tablets are prepared according to the following composition ratio. Raw materials and accessories Recipe 11 Puerarin 50.00mg microcrystalline cellulose 70.00mg Low-substituted hydroxypropyl cellulose 150.00mg sodium saccharin 10.00mg tartaric acid 5.00mg magnesium carbonate 6.00mg Sodium dodecyl sulfate 4.00mg Iron oxide (red) 0.001% 5% starch slurry Conventional amount Magnesium stearate 1%

The preparation steps are the same as in Example 1.

It is pressed on a tablet press, with an average tablet weight of about 300mg and a tensile strength of 20-50 Newtons.

The disintegration time limit and dissolution test method are the same as in Example 1. The disintegration time is about 26.55±3.40 seconds, and the dissolution rate is greater than 80% in 3 minutes.

The present invention is illustrated by the above description and examples, which are non-limiting and do not limit the scope of the claims of the present invention.

Claims (17)

1. A rapidly disintegrating and rapidly dissolving tablet containing puerarin, characterized in that it uses puerarin as an active ingredient, and also contains a mixture of excipients comprising a strong disintegrant and a strong solubilizer, the active The weight ratio of the mixture of ingredients and excipients is 1:1~1:50, the dosage of the active ingredient puerarin is 10~150 mg/tablet; the mixture of excipients includes fillers, disintegrants, Solubilizers, sweeteners, binders, lubricants, colorants and/or effervescent agents, wherein the amount of disintegrants is 2% to 20% of the total weight of the tablet, and the amount of solubilizers is 2% to 20% of the total weight of the tablet 1%~10%. 2. The rapidly disintegrating and rapidly dissolving tablet containing puerarin according to claim 1, wherein the dosage of the active ingredient puerarin is 20-100 mg/tablet. 3. The rapidly disintegrating and rapidly dissolving tablet containing puerarin according to claim 1, wherein the weight ratio of the mixture of the active ingredient and the excipient is 1:5~1:10. 4. The rapidly disintegrating and rapidly dissolving tablet containing puerarin according to claim 1, wherein said disintegrating agent is selected from the group consisting of crospovidone, croscarmellose sodium, carboxymethyl sodium starch glycolate, hydroxypropyl starch, low-substituted hydroxypropyl cellulose and mixtures thereof. 5. The rapidly disintegrating and rapidly dissolving tablet containing puerarin according to claim 1 or 4, characterized in that said disintegrant is crospovidone and/or croscarmellose sodium . 6. The rapidly disintegrating and rapidly dissolving tablet containing puerarin according to claim 1 or 4, characterized in that the dosage of the disintegrant is 5% to 15% of the total weight of the tablet. 7. The rapidly disintegrating and rapidly dissolving tablet containing puerarin according to claim 1, wherein said filler is microcrystalline cellulose, mannitol, lactose, xylitol, sucrose, glucose, starch , pregelatinized starch, calcium sulfate, calcium carbonate, calcium phosphate, light magnesium oxide and mixtures thereof. 8. The rapidly disintegrating and rapidly dissolving tablet containing puerarin according to claim 1 or 7, wherein said filler is microcrystalline cellulose, mannitol and lactose. 9. The rapidly disintegrating and rapidly dissolving tablet containing puerarin according to claim 1 or 7, wherein the filler accounts for 40%-90% of the total weight of the tablet. 10. The rapidly disintegrating and rapidly dissolving tablet containing puerarin according to claim 1 or 7, wherein the filler accounts for 60-80% of the total weight of the tablet. 11. The rapidly disintegrating and rapidly dissolving tablet containing puerarin according to claim 1, wherein said sweetener is aspartame, acesulfame potassium, sodium saccharin, Neohesperidin dihydrochalcone and mixtures thereof. 12. The rapidly disintegrating and rapidly dissolving tablet containing puerarin according to claim 1 or 11, characterized in that the dosage of the sweetener is 1% to 10% of the total weight of the tablet. 13. The rapidly disintegrating and rapidly dissolving tablet containing puerarin according to claim 1, wherein the effervescent agent is composed of an organic acid and a base, wherein the organic acid includes citric acid, tartaric acid, succinic acid, Lactic acid, glycolic acid, oxalic acid, gluconic acid, citric anhydride, succinic anhydride, tartaric anhydride and mixtures thereof, where bases include sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, calcium bicarbonate, magnesium carbonate, carbonic acid Barium and its mixtures. 14. The rapidly disintegrating and rapidly dissolving tablet containing puerarin according to claim 1 or 13, wherein the amount of the effervescent agent accounts for 0% to 40% of the total weight of the tablet. 15. The rapidly disintegrating and rapidly dissolving tablet containing puerarin according to claim 1, wherein the solubilizer includes poloxamers, Tweens, Spans, sodium lauryl sulfate , sodium cetyl sulfate, sodium octadecyl sulfate, sodium dioctyl sulfosuccinate, sodium dihexyl sulfosuccinate, sodium dodecylsulfonate, sodium dodecylbenzenesulfonate, glycerin Sodium cholate, sodium taurocholate, beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, niacinamide, benzoic acid, sodium benzoate and mixtures thereof. 16. The rapidly disintegrating and rapidly dissolving tablet containing puerarin according to claim 1 or 15, characterized in that said solubilizing agent is poloxamer and sodium lauryl sulfate. 17. The rapidly disintegrating and rapidly dissolving tablet containing puerarin according to claim 1 or 15, characterized in that the amount of the solubilizer is 2% to 5% of the total weight of the tablet.