Prescription of pentoxifylline sustained release tablet and preparation method of pentoxifylline sustained release tablet

Abstract

The invention belongs to the field of pharmaceutical preparations, and relates to a pentoxifylline sustained-release preparation, which comprises pentoxifylline as an active component, and a sustained-release material, an adhesive, a glidant and a lubricant as auxiliary materials, and the component of the slow-release skeleton is hydroxyethyl cellulose. Wherein each sustained-release tablet contains 200-700 parts by weight of pentoxifylline, and drug release is controlled by adding a sustained-release material; meanwhile, by adopting a secondary granulation technology, the drug release speed can be effectively slowed down, and the drug treatment time can be prolonged. The prescription preparation technology is simple and convenient, and commercialized production is easy to realize.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a prescription composition of a pentoxifylline sustained-release tablet and a preparation method thereof. Background Art

[0002] Pentoxifylline is a methyl purine derivative, with the chemical name 3,7-dihydro-3,7-dimethyl-1-(5-oxyhexyl)-1H-purine-2,6-dione, which is white powder or granules; it has a slight odor and tastes bitter; it is easily soluble in chloroform, soluble in water or ethanol, and slightly soluble in ether. As a non-selective phosphodiesterase inhibitor, the mechanism of action of pentoxifylline is to inhibit the activity of phosphodiesterase, thereby increasing the level of adenosine triphosphate (ATP) in cells. This increase can improve the deformability of red blood cells, reduce the production of fibrinogen, and inhibit the aggregation of red blood cells and platelets.

[0003] As a nonspecific dilator of peripheral blood vessels, pentoxifylline can dilate isolated canine basilar arteries, enhance the deformability of rat red blood cells, and improve the oxygen carrying capacity of tissues. In addition, it can reduce blood viscosity, increase capillary blood flow, improve blood fluidity, promote microcirculation, and provide more oxygen to ischemic tissues. Its metabolites also have the function of reducing blood viscosity and improving microcirculation.

[0004] After oral administration, pentoxifylline is rapidly and completely absorbed from the intestine. Its plasma half-life is approximately between 0.4 and 0.8 hours, while the half-life of metabolites is between 1 and 1.6 hours. After oral administration of common preparations, the time for plasma concentration to reach peak value is usually no more than 1 hour. Pentoxifylline is not bound to plasma proteins, is mainly metabolized in the liver, and is almost completely excreted in the urine in the form of metabolites.

[0005] Due to its first-pass effect, pentoxifylline is metabolized quickly in the body, resulting in a short half-life, which requires frequent administration of traditional oral preparations in clinical applications, and such frequent administration may lead to fluctuations and instability in the therapeutic effect.

[0006] To solve this problem, the development of pentoxifylline sustained-release tablets provides a solution. This sustained-release tablet prolongs the duration of drug action, reduces the frequency of administration, and avoids drastic fluctuations in blood drug concentration, thereby reducing the toxic side effects of the drug and improving the safety and convenience of treatment.

[0007] The preparation of sustained-release tablets uses hydrophilic gel skeleton technology. After oral administration, the skeleton material absorbs water and swells in the digestive fluid to form a gel barrier. Pentoxifylline can be gradually released outward through this gel layer. As the skeleton further swells, the gel layer gradually thickens, effectively slowing down the release rate of the drug and achieving slow and sustained release of the drug.

[0008] Through this design, the pentoxifylline sustained-release tablets not only improve the efficacy and safety of the drug, but also improve the patient's medication experience, making clinical treatment more efficient and convenient. Summary of the invention

[0009] The object of the present invention is to propose an improved pentoxifylline sustained-release tablet formulation and a production method thereof, aiming to overcome the limitations of the prior art and provide solutions to the problems identified in the above-mentioned background technology. The sustained-release tablet formulation contains pentoxifylline as an active ingredient, and sustained-release materials, adhesives, glidants and lubricants as excipients.

[0010] Furthermore, the model of hydroxyethyl cellulose is 250HHX, and the model of povidone is K30.

[0011] Specifically, the preparation method of the pentoxifylline sustained-release tablets of the present invention comprises the following steps: Step 1: Put the API, sustained-release material and binder into the granulation pot for mixing; Step 2: spray the wetting agent into the granulation pot to granulate, granulate, dry, and obtain dry granules①; Step 3: Add the dry granules into the granulation pot, spray the wetting agent into the granulation pot for granulation, granulation, drying, and obtaining dry granules②; Step 4: Add a flow aid to the dry granules ② and mix; Step 5: Add lubricant and mix thoroughly; Step 6: tabletting using a rotary tablet press; Step 7: coating. Another object of the present invention is to provide a method for preparing the above-mentioned tablets, comprising the following steps: Wherein, in step 1, in the mixing process, the speed of the stirring paddle is 150-300 rpm, the speed of the granulating knife is 300-500 rpm, and the mixing time is 3-5 min.

[0012] Furthermore, in step 2, in the granulation process, the stirring blade speed is 400-700 rpm, the granulating knife speed is 500-1000 rpm, the injection flow rate of the wetting agent is 35-70 g / min, the drying temperature is 45-60° C., and the granulation is granulated through a 14-20 mesh sieve.

[0013] Furthermore, in step 3, in the granulation process, the stirring blade speed is 400-700 rpm, the granulating knife speed is 500-1000 rpm, the injection flow rate of the wetting agent is 20-40 g / min, the drying temperature is 45-60° C., and the granulation is granulated through a 14-20 mesh sieve.

[0014] In step 4, the mixing time of the particles and the glidant is 5-10 minutes.

[0015] Furthermore, in step 5, the mixing time of the particles and the glidant is 3-5 minutes.

[0016] Exemplarily, in step 6, the tablet core hardness of the compressed tablet is 75-130N.

[0017] Exemplarily, the coating in step 7 is an Opadry coating solution with a solid content of 8-13%; the coating weight gain is 2-5%.

[0018] The excipients used in the sustained-release preparation of the present invention are all commonly used excipients, which have been registered and reviewed by the Food and Drug Administration, and have wide and reliable sources. In addition, the wet granulator is the most commonly used granulation equipment in pharmaceutical workshops. Therefore, the preparation of the present invention has low requirements and is easy to produce. DETAILED DESCRIPTION

[0020] The content of the present invention is further described by the embodiments of the present invention given below, but the present invention is not limited to the embodiments.

[0021] Example 1 prescription Unit dosage / mg Pentoxifylline 450 Hydroxyethylcellulose 160 Povidone K30 17 talcum powder 9 Magnesium Stearate 3 Wetting agent (first granulation) 300 Wetting agent (second granulation) 100 Preparation process: Add pentoxifylline, hydroxyethylcellulose, and povidone K30 to a wet granulator for premixing to make them uniformly dispersed. Spray purified water into the mixture of pentoxifylline, hydroxyethylcellulose and povidone K30 by atomization, wet granulation is performed, and then drying and granulation is performed; dry granules ① are obtained. Spray purified water into the dry granules ① by atomization, wet granulation is performed, and then drying and granulation is performed; dry granules ② are obtained. Talc and magnesium stearate are added to the dry granules in sequence and mixed; the obtained total mixed granules are tableted and coated to obtain pentoxifylline sustained-release tablets.

[0022] Example 2 prescription Unit dosage / mg Pentoxifylline 450 Hydroxyethylcellulose 160 Povidone K30 17 talcum powder 9 Magnesium Stearate 3 Wetting agent (first granulation) 250 Wetting agent (second granulation) 150 Preparation process: Add pentoxifylline, hydroxyethylcellulose, and povidone K30 to a wet granulator for premixing to make them uniformly dispersed. Spray purified water into the mixture of pentoxifylline, hydroxyethylcellulose and povidone K30 by atomization, wet granulation is performed, and then drying and granulation is performed; dry granules ① are obtained. Spray purified water into the dry granules ① by atomization, wet granulation is performed, and then drying and granulation is performed; dry granules ② are obtained. Talc and magnesium stearate are added to the dry granules ② in sequence and mixed; the obtained total mixed granules are tableted and coated to obtain pentoxifylline sustained-release tablets.

[0023] Example 3 prescription Unit dosage / mg Pentoxifylline 450 Hydroxyethylcellulose 160 Povidone K30 17 talcum powder 9 Magnesium Stearate 3 Wetting agent (first granulation) 200 Wetting agent (second granulation) 200 Preparation process: Add pentoxifylline, hydroxyethylcellulose, and povidone K30 to a wet granulator for premixing to make them uniformly dispersed. Spray purified water into the mixture of pentoxifylline, hydroxyethylcellulose and povidone K30 by atomization, wet granulation is performed, and then drying and granulation is performed; dry granules ① are obtained. Spray purified water into the dry granules ① by atomization, wet granulation is performed, and then drying and granulation is performed; dry granules ② are obtained. Talc and magnesium stearate are added to the dry granules ② in sequence and mixed; the obtained total mixed granules are tableted and coated to obtain pentoxifylline sustained-release tablets.

[0024] Example 4 prescription Unit dosage / mg Pentoxifylline 450 Hydroxyethylcellulose 160 Povidone K30 17 talcum powder 9 Magnesium Stearate 3 Wetting agent (first granulation) 150 Wetting agent (second granulation) 250 Preparation process: Add pentoxifylline, hydroxyethylcellulose, and povidone K30 to a wet granulator for premixing to make them uniformly dispersed. Spray purified water into the mixture of pentoxifylline, hydroxyethylcellulose and povidone K30 by atomization, wet granulation is performed, and then drying and granulation is performed; dry granules ① are obtained. Spray purified water into the dry granules ① by atomization, wet granulation is performed, and then drying and granulation is performed; dry granules ② are obtained. Talc and magnesium stearate are added to the dry granules ② in sequence and mixed; the obtained total mixed granules are tableted and coated to obtain pentoxifylline sustained-release tablets.

[0025] Example 5 prescription Unit dosage / mg Pentoxifylline 450 Hydroxyethylcellulose 160 Povidone K30 17 talcum powder 9 Magnesium Stearate 3 Wetting agent (first granulation) 100 Wetting agent (second granulation) 300 Preparation process: Add pentoxifylline, hydroxyethylcellulose, and povidone K30 to a wet granulator for premixing to make them uniformly dispersed. Spray purified water into the mixture of pentoxifylline, hydroxyethylcellulose and povidone K30 by atomization, wet granulation is performed, and then drying and granulation is performed; dry granules ① are obtained. Spray purified water into the dry granules ① by atomization, wet granulation is performed, and then drying and granulation is performed; dry granules ② are obtained. Talc and magnesium stearate are added to the dry granules ② in sequence and mixed; the obtained total mixed granules are tableted and coated to obtain pentoxifylline sustained-release tablets.

[0026] Example 6 prescription Unit dosage / mg Pentoxifylline 450 Hydroxyethylcellulose 160 Povidone K30 17 talcum powder 9 Magnesium Stearate 3 Wetting agent (first granulation) 250 Wetting agent (second granulation) 300 Preparation process: Add pentoxifylline, hydroxyethylcellulose, and povidone K30 to a wet granulator for premixing to make them uniformly dispersed. Spray purified water into the mixture of pentoxifylline, hydroxyethylcellulose and povidone K30 by atomization, wet granulation is performed, and then drying and granulation is performed; dry granules ① are obtained. Spray purified water into the dry granules ① by atomization, wet granulation is performed, and then drying and granulation is performed; dry granules ② are obtained. Talc and magnesium stearate are added to the dry granules ② in sequence and mixed; the obtained total mixed granules are tableted and coated to obtain pentoxifylline sustained-release tablets.

[0027] Comparative Example 1 prescription Unit dosage / mg Pentoxifylline 450 Hydroxyethylcellulose 160 Povidone K30 17 talcum powder 9 Magnesium Stearate 3 Wetting Agents 200 Preparation process: Add pentoxifylline, hydroxyethylcellulose and povidone K30 into a wet granulator for premixing to make them uniformly dispersed. Spray purified water into the mixture of pentoxifylline, hydroxyethylcellulose and povidone K30 by atomization, wet granulate, and then dry and granulate to obtain dry granules. Add talcum powder and magnesium stearate to the dry granules in sequence and mix well; the obtained total mixed granules are tableted and coated to obtain pentoxifylline sustained-release tablets.

[0028] Comparative Example 2 prescription Unit dosage / mg Pentoxifylline 450 Hydroxyethylcellulose 160 Povidone K30 17 talcum powder 9 Magnesium Stearate 3 Wetting Agents 30 Preparation process: Add pentoxifylline, hydroxyethylcellulose and povidone K30 into a wet granulator for premixing to make them uniformly dispersed. Spray purified water into the mixture of pentoxifylline, hydroxyethylcellulose and povidone K30 by atomization, wet granulate, and then dry and granulate to obtain dry granules. Add talcum powder and magnesium stearate to the dry granules in sequence and mix well; the obtained total mixed granules are tableted and coated to obtain pentoxifylline sustained-release tablets.

[0029] ]Dissolution assay: Take the samples of Example 1-6 and Comparative Example 1-2, refer to the Chinese Pharmacopoeia, use the paddle method, at 37°C, 50rpm, with 900ml of hydrochloric acid solution (9→1000) as the dissolution medium, sample 10ml at 2, 6, 12, and 16h, and immediately replenish the dissolution medium of the same temperature and volume. Take the dissolution solution at 2 hours, 6 hours, 12 hours, and 16 hours, filter, and accurately measure 3.0ml, 1.0ml, 1.0ml, and 1.0ml of the filtrate, put it in a 25ml volumetric bottle, add the dissolution medium to dilute to the scale, shake well, and measure the absorbance at a wavelength of 274nm according to the ultraviolet-visible spectrophotometry (General Rule 0401), and calculate the dissolution amount of each tablet at different times according to the absorption coefficient of C13H18N4O3 of 351.

[0030] The reference preparation was pentoxifylline sustained-release tablets (Trental) produced by Sanofi, batch number 2U004.

[0031] As can be seen from the above table, the dissolution results of Examples 1-6 show that the sustained-release effect of the pentoxifylline sustained-release tablets prepared according to the present invention is stable, the dissolution curve is consistent with the reference preparation, and the in vitro dissolution standard required by the pharmacopoeia is met.

[0032] The pentoxifylline sustained-release tablets of the present invention show excellent sustained-release properties in vitro, matching the dissolution behavior of the original drug. This finding indicates that when the drug is used in clinical treatment, it has the potential to reduce the frequency of medication for patients, reduce possible side effects, and enhance the safety of treatment.

Claims

1. A prescription and preparation method of pentoxifylline sustained-release tablets, characterized in that The preparation method comprises the following raw materials in parts by weight: 200-700 parts of pentoxifylline, 90-170 parts of sustained-release material, 5-20 parts of binder, 1-20 parts of glidant, 1-20 parts of lubricant, 100-300 parts of wetting agent added in the first granulation, and 100-300 parts of wetting agent added in the second granulation.

2. A pentoxifylline sustained-release tablet according to claim 1, characterized in that The sustained-release material is hydroxyethyl cellulose.

3. The pentoxifylline sustained-release tablet according to claim 1, characterized in that: The binder is povidone.

4. The pentoxifylline sustained-release tablet according to claim 1, characterized in that: The glidant is talc.

5. The pentoxifylline sustained-release tablet according to claim 1, characterized in that: The lubricant is magnesium stearate.

6. The pentoxifylline sustained-release tablet according to claim 1, characterized in that: The wetting agent is purified water.

7. A method for preparing a pentoxifylline sustained-release tablet according to claim 1, characterized in that The pentoxifylline, the sustained-release material and the binder are added to a wet granulator for premixing to make them uniformly dispersed. The wetting agent is sprayed into the mixture of the pentoxifylline, the sustained-release material and the binder by atomization, wet granulation is performed, and then drying and granulation are performed; dry granules are obtained. The wetting agent is sprayed into the dry granules by atomization, secondary wet granulation is performed, and then drying and granulation are performed; dry granules are obtained. A lubricant is added to the dry granules and mixed; the obtained total mixed granules are tableted and coated to obtain pentoxifylline sustained-release tablets.

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