CN102091051B - Allopurinol dual-release preparation and preparation method thereof - Google Patents

Abstract

The invention relates to an allopurinol double-release preparation and a preparation method thereof, which is characterized in that the double-release preparation is composed of an immediate-release part and a sustained-release part, wherein the immediate-release part and the sustained-release part contain the main drug allopurinol The specific gravity is 1:1-1:24. It belongs to the technical field of pharmaceutical preparations. The object of the present invention is to provide an allopurinol double-release preparation with good patient compliance, less side effects, rapid onset of action and long-lasting maintenance of stable and effective blood drug concentration and a preparation method thereof. The double-release preparation not only reduces the side effects on the gastrointestinal tract, but also reduces the number of medications taken by patients, reduces adverse reactions, and improves patient compliance.

Description

A kind of allopurinol double-release preparation and preparation method thereof

technical field

The invention relates to an allopurinol double-release preparation and a preparation method thereof, which is characterized in that the double-release preparation is composed of an immediate-release part and a sustained-release part, wherein the immediate-release part and the sustained-release part contain the main drug allopurinol The specific gravity is 1:1-1:24. It belongs to the technical field of pharmaceutical preparations.

Background technique

Allpurinol has a chemical structure of 1H-pyrazolo[3,4-d]pyrimidin-4-ol. Allopurinol is white or off-white crystalline powder; almost odorless and tasteless. Very slightly soluble in water or ethanol, insoluble in ether or chloroform; dissolved in alkaline solution. Allopurinol is currently the only drug that can inhibit the synthesis of uric acid. It and its metabolite oxypurinol inhibit the activity of xanthine oxidase, prevent the metabolism of hypoxanthine and xanthine into uric acid, and reduce the uric acid content in blood and urine to Solubility below the level, thereby preventing uric acid from forming crystals and depositing in joints and other tissues, and also helping to redissolve uric acid crystals in the tissues of gout patients. Allopurinol can also inhibit the synthesis of new purines in the body through the action on hypoxanthine-guanine phosphate nucleic acid conversion enzyme. After oral administration, allopurinol is completely absorbed in the gastrointestinal tract and metabolized into active oxypurinol in the liver, neither of which can bind to protein. The half-life of allopurinol is 1 to 3 hours, and it is excreted by the kidneys together with oxypurinol.

At present, allopurinol that has been marketed in China is an ordinary tablet, which generally needs to be taken 1 to 3 times a day, and it cannot maintain a stable and effective anti-gout blood drug concentration, and the action time is short. In addition, the peak blood concentration of ordinary tablets fluctuates greatly, which is prone to adverse reactions. In view of the above shortcomings of ordinary tablets, in order to better control the blood concentration of allopurinol, ensure clinical efficacy, reduce the number of medications, improve compliance, and reduce the occurrence of adverse reactions, a double-release preparation of allopurinol was developed.

Beneficial effect

1. The allopurinol double-release preparation has developed its advantages and improved the shortcomings of commonly used dosage forms, because it consists of an immediate-release part and a sustained-release part. After oral administration, the allopurinol in the immediate-release part dissolves rapidly and reaches an effective blood concentration. The rapid onset of action, and the slow release of the sustained release part, can maintain an effective and stable blood drug concentration for a long period of time, so that the drug effect can be maintained for 12-24 hours.

2. It can reduce the side effects of drugs on the gastrointestinal tract. Conventional preparations are taken in a large amount and are highly irritating to the gastrointestinal tract, and making sustained-release preparations can reduce side effects.

3. The release time of the drug is significantly prolonged, thereby reducing the number of times of taking the drug, improving patient compliance, and reducing irritation and adverse reactions.

Contents of the invention

An object of the present invention is to provide an allopurinol double-release preparation with good patient compliance, less side effects, rapid onset of action and long-term maintenance of stable and effective blood drug concentration.

Another object of the present invention is to provide a preparation method of allopurinol double release preparation.

The present invention relates to an allopurinol double-release preparation, which is characterized in that the double-release preparation is composed of an immediate-release part and a sustained-release part, wherein the immediate-release part and the sustained-release part contain the main drug allopurinol at a ratio of 1: 1-1:24, the immediate release part contains the main drug allopurinol and disintegrants, diluents, binders, lubricants; the sustained release part contains the main drug allopurinol and sustained release materials, diluents, binders, lubricants agent.

The double-release preparation of the present invention is characterized in that the immediate-release part in the double-release preparation is by weight percentage: allopurinol accounts for 15% to 75%, preferably 25% to 65%; the diluent accounts for 5% to 50% %, preferably 15% to 40%; disintegrants account for 5% to 50%, preferably 10% to 40%; binders 0.5% to 15%, preferably 2% to 10%; lubricants account for 0.01% to 3.0% .

The double-release preparation of the present invention is characterized in that the slow-release part in the double-release preparation is by weight percentage: 30% to 80% of allopurinol, preferably 30% to 70%; the slow release material accounts for 5% to 40% %, preferably 10% to 25%; diluent 5% to 30%, preferably 10% to 20%; binder 1% to 10%, preferably 3% to 8%; lubricant 0.1% to 3.0%.

The dual-release preparation of the present invention is characterized in that the sustained-release material is selected from hypromellose, hydroxypropyl cellulose, sodium alginate, sodium carboxymethyl cellulose, povidone, copovidone , polypropylene alcohol, ethyl cellulose, hydroxyethyl cellulose, polyacrylic acid resin polymer, stearic acid, carnauba wax in one or more, preferably hydroxypropyl methyl cellulose.

The dual-release formulation of the present invention is characterized in that the diluent is selected from microcrystalline cellulose, mannitol, starch, powdered sugar, pregelatinized starch, low-substituted hydroxypropyl cellulose, polyethylene glycol, One or more of ethanol, preferably microcrystalline cellulose.

The dual-release formulation of the present invention is characterized in that the disintegrant is selected from cross-linked polyvinylpyrrolidone, povidone, cross-linked povidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, One or more of starch and croscarmellose sodium, preferably sodium carboxymethyl starch or starch.

The dual-release formulation of the present invention is characterized in that the binder is selected from povidone, copovidone, hypromellose, starch, sodium carboxymethyl starch, ethyl cellulose, polyacrylic acid One or more resinous polymers, preferably povidone.

The dual-release formulation of the present invention is characterized in that the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, hard sodium fumarate, micronized silica gel, talcum powder, and lauryl magnesium sulfate. One or more, preferably magnesium stearate.

The dual-release formulation of the present invention is characterized in that it comprises the following preparation steps:

(1) Preparation of immediate-release granules: crush allopurinol through an 80-mesh sieve, and set aside; weigh allopurinol, disintegrant, binder, and diluent in the prescribed amount, mix well, add appropriate amount of water, and carry out wet preparation Granules, 16-mesh sieve wet granulation, 50 ° C drying, 20-mesh sieve granulation, calculate the yield, add magnesium stearate, mix, set aside.

(2) Preparation of sustained-release granules: pulverize allopurinol through an 80-mesh sieve for subsequent use; weigh the allopurinol, sustained-release material, and diluent of the prescribed amount, mix well, add the soft material prepared with adhesive, Carry out wet granulation, wet granulation with 16 mesh sieve, dry at 50°C, granulate with 20 mesh sieve, calculate yield, add magnesium stearate, mix, set aside.

(3) Mix the granules prepared in (1) and (2) evenly, and directly pack into capsules to obtain sustained-release capsules.

(4) Add the granules prepared in (1) to the hopper on one side of the double-layer tablet press equipment, start the tablet press, and adjust the tablet weight and hardness (0-5kg); then add the granules prepared in (2) to The hopper on the other side of the double-layer tablet pressing equipment adjusts the weight and hardness of the tablet, and performs continuous compression to obtain a double-layer sustained-release tablet.

Description of drawings

Fig. 1 is the slow-release capsule release rate curve chart that embodiment 1-5 makes

Fig. 2 is the curve diagram of the double-layer slow-release tablet that embodiment 1-5 makes

Detailed ways

Example 1:

quick release part

Allopurinol 50g

Microcrystalline Cellulose 101 20g

Starch 30g

Povidone K30 3g

Magnesium stearate 0.5g

Sustained release part

Allopurinol 200g

Hypromellose K100LV 40g

Microcrystalline Cellulose 101 50g

Povidone K30 15g

Magnesium stearate 0.8g

Made into 1000 pieces/grain

Preparation:

(1) Preparation of immediate-release granules: crush allopurinol through an 80-mesh sieve, and set aside; weigh allopurinol, starch, povidone K30, and microcrystalline cellulose 101 of the prescribed amount, mix well, add appropriate amount of water, and carry out Wet granulation, wet granulation with a 16-mesh sieve, drying at 50°C, granulation with a 20-mesh sieve, calculate the yield, add magnesium stearate, mix, and set aside.

(2) Preparation of sustained-release granules: crush allopurinol through an 80-mesh sieve, and set aside; weigh allopurinol, microcrystalline cellulose 101, and hypromellose K100LV in the prescribed amount, mix well, and add 20% polyvinyl alcohol An appropriate amount of ketone K30 ethanol solution is used for wet granulation, wet granulated with a 16-mesh sieve, dried at 50°C, granulated with a 20-mesh sieved, calculated yield, added magnesium stearate, mixed, and set aside.

(3) Mix the granules prepared in (1) and (2) evenly, and directly pack into capsules to obtain sustained-release capsules.

(4) Add the granules prepared in (1) to the hopper on one side of the double-layer tablet press equipment, start the tablet press, and adjust the tablet weight and hardness (0-5kg); then add the granules prepared in (2) to The hopper on the other side of the double-layer tablet pressing equipment adjusts the weight and hardness of the tablet, and performs continuous compression to obtain a double-layer sustained-release tablet.

Example 2:

Quick release part:

Allopurinol 50g

Microcrystalline Cellulose 101 25g

Starch 26g

Povidone K30 3.7g

Magnesium stearate 0.5g

Sustained release part

Allopurinol 200g

Hypromellose K4M 25g

Hypromellose E5 26g

Microcrystalline Cellulose 101 45g

Povidone K30 15g

Magnesium stearate 0.8g

Made into 1000 pieces/grain

Preparation method: with embodiment 1.

Example 3:

Quick release part:

Allopurinol 125g

Microcrystalline Cellulose 101 38g

Sodium carboxymethyl starch 23g

Povidone K ₃₀ 12g

Magnesium Stearate 1g

Sustained release part:

Allopurinol 125g

Hypromellose K100LV 55g

Microcrystalline Cellulose 101 40g

Povidone K ₃₀ 15g

Magnesium Stearate 1g

A total of 1000 pieces/grain were made

Preparation method: with embodiment 1.

Example 4:

Quick release part:

Allopurinol 100g

Microcrystalline Cellulose 101 35g

Starch 15g

Povidone K ₃₀ 10g

Magnesium stearate 0.8g

Sustained release part:

Allopurinol 150g

Hypromellose K4M 45g

Hypromellose E5 26g

Microcrystalline Cellulose 101 48g

Povidone K ₃₀ 16g

Magnesium stearate 1g

A total of 1000 pieces/grain were made

Preparation method: with embodiment 1.

Example 5:

Quick release part:

Allopurinol 25g

Microcrystalline Cellulose 101 15g

Sodium carboxymethyl starch 20g

Povidone K30 3g

Magnesium stearate 0.5g

Sustained release part

Allopurinol 225g

Hypromellose K4M 48g

Hypromellose E5 27g

Microcrystalline Cellulose 101 50g

Povidone K30 18g

Magnesium stearate 1g

Made into 1000 pieces/grain

Preparation method: with embodiment 1.

Embodiment 6:

Quick release part:

Allopurinol 12.5g

Microcrystalline Cellulose 101 12g

Sodium carboxymethyl starch 17g

Povidone K30 2.5g

Magnesium stearate 0.5g

Sustained release part

Allopurinol 237.5g

Hypromellose K100LV 60g

Microcrystalline Cellulose 101 45g

Povidone K30 15g

Magnesium Stearate 1g

Made into 1000 pieces/grain

Preparation method: with embodiment 1.

Embodiment 7:

Immediate-release layer prescription (according to 1000 tablets):

Allopurinol 10g

Microcrystalline Cellulose 101 20g

Starch 10g

Povidone K30 3g

Magnesium stearate 0.5g

Sustained-release layer prescription (according to 1000 tablets)

Allopurinol 240g

Hypromellose K4M 36g

Hypromellose E5 28g

Microcrystalline Cellulose 101 50g

Povidone K30 15g

Magnesium stearate 0.8g

Made into 1000 pieces

Preparation method: with embodiment 1.

In order to investigate the in vitro release effect of the present invention, according to the release assay method (Chinese Pharmacopoeia version in 2005 two appendix X D first method), the first method of dissolution device is adopted, with 0.1mol/L hydrochloric acid solution 900ml as solvent, rotating speed 75 revolutions per minute, operate according to the law, take 10ml of the solution at 1 hour, 4 hours and 8 hours, filter, and immediately replenish the release medium of the same volume and temperature in the dissolution vessel, dilute the subsequent filtrate as the The test solution was tested for release.

The release results of the sustained-release capsules prepared in Examples 1-5 are shown in Table 1, and the release results of the double-layer sustained-release tablets are shown in Table 2.

The sustained-release capsule release test result that table 1 embodiment 1-5 makes

1 hour 4 hours 8 hours Example 1 31.5% 63.5% 94.0% Example 2 30.4% 61.4% 92.2% Example 3 36.5% 55.3% 87.4% Example 4 34.8% 53.7% 88.9% Example 5 20.1% 48.9% 83.1%

The double-layer slow-release tablet dissolubility test result that table 2 embodiment 1-5 makes

1 hour 4 hours 8 hours Example 1 28.3% 60.4% 90.2%

Example 2 27.8% 58.9% 89.5% Example 3 32.9% 51.8% 84.7% Example 4 30.8% 51.7% 83.9% Example 5 18.1% 45.9% 79.1%

Claims (7)

1. two delivery formulations of an allopurinol, it is characterized in that described pair of delivery formulations is to be made of immediate release section and slow-released part, wherein to contain the proportion of principal agent allopurinol be 1:1-1:24 for immediate release section and slow-released part, and immediate release section contains principal agent allopurinol and disintegrating agent, diluent, binding agent, lubricant; Slow-released part contains principal agent allopurinol and slow-release material, diluent, binding agent, lubricant, wherein, immediate release section by weight percentage: allopurinol accounts for 15%～75%, diluent accounts for 5%～50%, disintegrating agent accounts for 5%～50%, binding agent 0.5%～15%, and lubricant accounts for 0.01%～3.0%; Slow-released part is by weight percentage: allopurinol 30%～80%, and slow-release material accounts for 5%～40%, diluent 5%～30%, binding agent accounts for 1%～10%, and lubricant accounts for 0.1%～3.0%;

And, described slow-release material is selected from hypromellose, hydroxypropyl cellulose, sodium alginate, sodium carboxymethyl cellulose, polyvidone, copolyvidone, POLYPROPYLENE GLYCOL, ethyl cellulose, hydroxyethyl-cellulose, the polyacrylic resin base polymer, stearic acid, in the Brazil wax one or more, described diluent is selected from microcrystalline Cellulose, mannitol, starch, Icing Sugar, pregelatinized Starch, low-substituted hydroxypropyl cellulose, Polyethylene Glycol, in the ethanol one or more, described disintegrating agent is selected from crospolyvinylpyrrolidone, polyvidone, polyvinylpolypyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, starch, in the cross-linking sodium carboxymethyl cellulose one or more, described binding agent is selected from polyvidone, copolyvidone, hypromellose, starch, carboxymethyl starch is received, ethyl cellulose, in the polyacrylic resin base polymer one or more, described lubricant agent is selected from magnesium stearate, calcium stearate, the hard fumaric acid sodium, micropowder silica gel, Pulvis Talci, the moon is hung one or more in the pure magnesium sulfate.

2. the two delivery formulations of allopurinol claimed in claim 1 is characterized in that, immediate release section by weight percentage allopurinol accounts for 25%～65%, and diluent accounts for 15%～40%, disintegrating agent 10%～40%, and binding agent 2%～10%, lubricant accounts for 0.01%～3.0%.

3. claimed in claim 1 pair of delivery formulations, it is characterized in that slow-released part by weight percentage in the described pair of delivery formulations: allopurinol accounts for 30%～70%, and slow-release material accounts for 10%～25%, and diluent accounts for 10%～20%, binding agent accounts for 3%～8%, and lubricant accounts for 0.1%～3.0%.

4. each described pair of delivery formulations of claim 1-3, described slow-release material is hydroxypropyl methylcellulose, and described diluent is microcrystalline Cellulose, and described disintegrating agent is carboxymethyl starch sodium, starch, described binding agent is polyvidone, and described lubricant is magnesium stearate.

5. each described pair of delivery formulations of claim 1-4 is characterized in that calculating by weight, and it consists of:

6. each described pair of delivery formulations of claim 1-4 is characterized in that calculating by weight, and it consists of:

7. each described pair of delivery formulations of claim 1-6 is characterized in that comprising and is prepared as follows step:

(1) immediate-release granules preparation: allopurinol was pulverized 80 mesh sieves, for subsequent use; Take by weighing allopurinol, disintegrating agent, binding agent, the diluent of recipe quantity, mix homogeneously adds suitable quantity of water, carries out wet granulation, the 16 mesh sieves granulate that wet, and 50 ℃ of oven dry, 20 mesh sieve granulate, calculated yield adds magnesium stearate, and mixing is for subsequent use;

(2) slow-releasing granules preparation: allopurinol was pulverized 80 mesh sieves, for subsequent use; Take by weighing allopurinol, slow-release material, the diluent of recipe quantity, mix homogeneously adds the soft material that makes with binding agent, carries out wet granulation, the 16 mesh sieves granulate that wet, and 50 ℃ of oven dry, 20 mesh sieve granulate, calculated yield adds magnesium stearate, and mixing is for subsequent use;

(3) with the granule mix homogeneously of (1) and (2) preparation, directly encapsulated, namely get slow releasing capsule;

(4) granule that (1) is made adds a side hopper of putting Double layer pellet equipment, starts tablet machine, and adjustment sheet weighs and hardness 5kg; The granule that again (2) is made adds the opposite side hopper of putting Double layer pellet equipment, and adjustment sheet weighs and hardness, suppresses continuously, namely gets double-layer sustained release tablets.

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