CN1994285B - Sustained release micro-pellet of guaifenesin and preparation process thereof - Google Patents

Abstract

The invention discloses a guaiacol glycerin sustained-release pellet and a preparation method thereof. The guaiacol glycerin sustained-release pellets of the present invention are composed of a drug-loaded pellet core loaded with therapeutically effective active ingredients and pharmaceutical auxiliary materials, a sustained-release coating layer and an immediate-release drug layer from the inside to the outside. The drug-loaded pill core with high drug loading is prepared by extrusion spheronization technology, and then wrapped with an immediate-release coating layer after coating. Ethyl cellulose is the preferred material for the sustained-release coating layer, and the coating is carried out in a fluidized state, and the drug-containing immediate-release coating layer is evenly coated in the same device. The guaiacol glycerin sustained-release pellets prepared by the process can release medicine for 12 hours. The preparation has good process reproducibility, has two parts of immediate release and sustained release, and the release mode is stable and reliable.

Description

Guaifenesin sustained-release pellets and preparation method thereof

technical field

The invention relates to the field of pharmaceutical preparations, in particular to guaiacol glycerin sustained-release pellets capable of sustained release for 12 hours and a preparation method thereof.

Background technique

The main source of sputum is secretion from tracheobronchial glands and goblet cells. In pathological conditions such as respiratory tract inflammation, mucus cannot be transported out in time due to excessive secretion due to inflammatory stimulation, or decreased cilia activity due to mucosal epithelial lesions, or pathological changes in sputum components that increase viscosity. A large amount of sputum obstructing the airway can cause shortness of breath and even suffocation. On the other hand, sputum is a good culture medium, which is conducive to the growth of pathogens and cause secondary infections. Therefore, expectorant discharge is one of the important symptomatic treatment measures.

Guaifenesin is one of the nauseous expectorant drugs. After oral administration, it can stimulate the gastric mucosa, reflexively increase bronchial secretion, and reduce the viscosity of sputum. Clinically, it is mainly used to eliminate phlegm. Although this drug has been used for a long time, it has always been an important drug that is difficult to replace in expectorant drugs.

The adult dose of guaiacol glycerin is 200-400 mg, once every 4 hours (Martindale: The Extra Pharmacopoeia 32ed. Pharmaceutical Press 1999, P1061). Frequent dosing times cause problems for patient compliance, especially affecting nighttime sleep. US 6372252 disclosed a related invention patent of guaiacol glyceryl ether sustained-release tablet in 2002. The patent takes the form of a bilayer tablet, with the drug dispersed in the immediate-release and sustained-release matrix of the tablet. After the patient takes medication, the immediate-release part of the drug is released first to maintain a rapid therapeutic effect, and then the drug in the sustained-release matrix is gradually released. The drug effect time can be maintained for 12 hours after administration.

Although the double-layer tablet described in the above-mentioned patent has the advantages of convenient administration and reasonable and reliable drug release mode in the body, the preparation in the patent is too large (the weight of each tablet is about 1600 mg or more), which is not conducive to those who have difficulty swallowing, such as Drugs for children and the elderly. Because of its special composition and structure, the bilayer tablet cannot be chewed or broken or swallowed by patients during the medication process, which limits the application of this preparation in the general population.

It is also mentioned in the above-mentioned patent that pellets can be used to solve the slow release of guaiacol glyceryl ether. The patent applicant discusses the use of two pellets with different release rates: one is an immediate-release pellet and the other is a sustained-release pellet. Fill in hard capsules after mixing in different proportions. The patent does not discuss how to prepare these two types of pellets, and the applicant is only ambiguous. It seems that the components similar to those in the double-layer tablet, that is, hydrophilic polymers can be mixed with part of the drug to form immediate-release parts; The polymer is blended with another part of the drug and granulated into the sustained release part, and then the two parts of the granules are blended to obtain a similar pattern of drug release in vivo as bilayer tablets are administered.

The latter preparation described by the US patent applicant is actually proposed from the strategy of expanding the scope of patent protection, rather than an experimental-based preparation method. From a professional point of view, it is impossible to make sustained-release pellets with this technology. The reasons are as follows:

1. Glyceryl ether is a highly water-soluble drug. In the preparation applied by the patent applicant, the drug dose is 1200 mg, and according to the patent introduction, the preparation weighs about 1300 mg. Whether the pill adopts the skeleton technology or the membrane control technology, it is impossible to control the slow release of water-soluble drugs for up to 12 hours.

2. According to the patent applicant, the quick-release part of the drug is 400 mg, and the slow-release part of the drug is 800 mg; according to this idea, if made into pellets, 1/3 of them are quick-release pellets, and 2/3 are slow-release pellets. According to the idea of the patent applicant, the former type of pellet is granulated by mixing the drug with a hydrophilic polymer, and the latter is granulated by mixing the drug with a hydrophobic polymer (or mixed with other auxiliary materials and granulated before coating). The proportions of the two particle drugs are different, and the excipients are different, so the specific gravity of the pellets must be quite different. The uniformity of mixing will be a problem like this, which will inevitably affect the drug release mode in vivo.

Contents of the invention

The technical problem to be solved by the present invention is to provide a kind of guaiacol glyceryl ether sustained-release pellets and its preparation method. The sustained-release pellets are composed of slow-release and quick-release parts on each individual pellet to control drug release. Up to 12 hours, can thoroughly solve the problems of the two preparations of the US patent.

The guaiacol glycerin sustained-release pellets of the present invention are composed of drug-loaded pellet cores, sustained-release coating layers and immediate-release drug layers loaded with therapeutically effective active ingredients and pharmaceutical excipients from the inside to the outside; the active The ingredient is guaiacol glyceryl ether, and the pharmaceutical excipients include one or a mixture of microcrystalline cellulose, hydroxypropylmethylcellulose, povidone, hydroxypropylcellulose or sodium carboxymethylcellulose; The sustained-release coat layer is ethyl cellulose series polymer or polyacrylic acid series polymer; the quick-release drug layer is composed of guaiacol glyceryl ether and selected from hydroxypropyl methylcellulose, hydroxypropyl One of cellulose, sodium carboxymethyl cellulose or povidone or a mixture thereof.

The drug in the drug-loaded ball core can account for 50-90% of the weight of the ball core. Microcrystalline cellulose (MCC) is the best choice for the main and auxiliary material of the core part of the skeleton, preferably PH101 specification, and its dosage is 10-50% based on the weight of the pellet core. Use MCC similar to RC581 and RCS91. In addition to MCC, other excipients such as calcium hydrogen phosphate, lactose, glucose, sucrose, citric acid, maleic acid, succinic acid, boric acid, etc. can also be mixed into the skeleton.

Drugs and skeleton accessories must be added to the binder aqueous solution to make soft materials with good plasticity. The binder can be a semi-synthetic cellulose derivative, such as an aqueous solution of low-viscosity hydroxypropyl cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose sodium (CMC-Na), or Povidone (PVP) aqueous solution. According to the difference of material viscosity, ethanol can be added to the above polymer solution to adjust as appropriate.

公司的Eudragit系列(Eudragit RS，Eudragit RL或Eudragit NE30D等)。采用Eudragit NE30D，衣材增重(相对载药丸芯重量)为2～10％，优选为4～6％；采用Eudragit RS/RL衣材增重(相对载药丸芯重量)为2～10％，优选为5～8％，可选择95％乙醇为溶剂。衣材中应加入致孔剂，如低粘度HPMC、PEG或PVP等，其用量相当于衣材重的15～25％。衣材中也应加入增塑剂，如柠檬酸三乙酯(TEC)、葵二酸二丁酯、甘油三醋酸酯等。衣材中也可加入抗粘剂，如滑石粉等。When HPMC and PVP aqueous solution are used as binders, the concentration (w/v) can be taken as 5% according to different situations. When CMC-Na is used as binder, the concentration can also be taken as 1-5%. The sustained-release coating layer of the drug-loaded pellet core can be polyacrylic resin such as German

The company's Eudragit series (Eudragit RS, Eudragit RL or Eudragit NE30D, etc.). Using Eudragit NE30D, the weight gain of the clothing material (relative to the weight of the drug-loaded pellet core) is 2-10%, preferably 4-6%; the weight gain of the Eudragit RS/RL clothing material (relative to the weight of the drug-loaded pellet core) is 2-10%, It is preferably 5-8%, and 95% ethanol can be selected as the solvent. A porogen, such as low-viscosity HPMC, PEG or PVP, should be added to the clothing material in an amount equivalent to 15-25% of the weight of the clothing material. Plasticizers should also be added to the clothing, such as triethyl citrate (TEC), dibutyl sebacate, triacetin, etc. Anti-adhesive agents, such as talcum powder, can also be added to the clothing.

Ethyl cellulose series (Surelease from Colorcon Corporation of the United States or Aqnacoat of FMC Corporation of the United States) etc. can also be used for the sustained-release coating layer of the drug-loaded pellet core. With Surelease, the weight gain of clothing materials is 2-10%, preferably 5-8%. A porogen, such as low-viscosity HPMC, PEG or PVP, can be added to the clothing in an amount equivalent to 15-25% of the weight of the clothing. The plasticizer and other auxiliary materials in Surelease have been pre-mixed by the manufacturer, so in principle there is no need to add them.

In order to improve the surface smoothness of the pellets, an isolation layer can be wrapped with low-viscosity HPMC, and its thickness is 2-5% of the weight gain of the drug-loaded pellets. If the roundness and smoothness of the pellets are good, the isolation layer may not be used.

In order to ensure that there is an immediate-release drug dose after the medication, in addition to wrapping the drug-loaded pill core skeleton with a sustained-release coat layer, the periphery will be coated with an immediate-release drug layer. The drug content of this layer may be 10-20% of the dose.

The preparation method of the guaiacol glycerin sustained-release pellets of the present invention comprises the following steps:

(1) After the calculated amount of medicine is mixed with pharmaceutical excipients, a binder is added to make a soft material, and the soft material is made into a drug-loaded pill core through an extrusion device;

(2) The drug-loaded pill core is coated with a slow-release coating layer by the pot-packing method or fluidized bed technology to obtain a slow-release drug-loaded pellet;

(3) Slow-release drug-loaded pellets are coated with an immediate-release drug layer in a coating device, dried to allow the coating film to heal, and then sieved to obtain the guaiacol sustained-release pellets of the present invention.

The soft material made of drugs and excipients can be made into particles with a certain particle size through an extrusion device. The extrusion device can be a screw extrusion type or a rotary drum extrusion type. The particle size of the extruded product is controlled by the aperture of the terminal sieve plate or the aperture of the roller, and the speed of the extrusion shaft is 50-150rpm. If the speed is too fast, the temperature of the soft material will rise due to the heat generated by mechanical friction, and the water will evaporate, causing initial and subsequent extrusion. Due to the difference in the humidity of the material, the spheronization will cause problems such as the difference in the quality of the pellet core.

The speed and time of the spheronization step and the loading of the extruded product have a certain relationship with the particle size and distribution of the pellets, the roundness and density of the pellet core. This method adopts a laboratory spheronization device, the rotating speed is controlled at 800-1200rpm, the loading capacity is 30-100g, and the spheronization time is about 1.5-5 minutes.

After coating the pellets, the coating film must be cured, and heat treatment is most commonly used for curing. The common method is to use small pellets in a pan oven, and dynamic processing can also be used. The pellets are healed in the hot air flow in the fluidized bed. During the healing process, the coating layer gradually changes from a discontinuous state to a continuous film layer, and the degree of film layer healing affects the drug release rate.

Since the sustained-release pellets are composed of slow-release and rapid-release parts on each individual pellet, after the patient takes medication, the drug in the immediate-release drug layer is released first to maintain a rapid therapeutic effect, and then the drug in the drug-loaded pellet core is gradually released. . The long-term release of the drug can be maintained after medication, which solves the inconvenience of frequent medication of conventional guaiacol and the unfavorable problems of human body treatment caused by the peak-valley phenomenon of blood drug concentration. Therefore the advantage of the guaiacol glyceryl ether sustained-release pellets of the present invention is very significant, and the sustained-release pellets of the present invention are also beneficial to those with dysphagia such as children and the elderly, so that the preparation of the U.S. patent has been completely solved. Existing problems. The prepared sustained-release pellets were carried out in vitro drug release experiment according to method 1 in the second method of the second method of the Chinese Pharmacopoeia 2005 edition of the release rate assay, and the results showed that the guaiacol glyceryl ether sustained-release pellets released by this process could Lasts 12 hours. The preparation process has good reproducibility, and the drug release mode is stable and reliable.

Detailed ways

Example 1

Pill Loaded Prescription:

Guaifenesin 180g

Microcrystalline Cellulose 20g

Extended Release Coating Prescription:

Surelease 80g

Hydroxypropyl Methyl Cellulose 4g

Immediate Release Coating Prescription:

Guaifenesin 45g

Hydroxypropyl methylcellulose 4.5g (10%)

I. Preparation of drug-loaded pellet cores by extrusion and spheronization to prepare drug-loaded pellet cores

(1) According to the prescription quantity, mix the microcrystalline cellulose and guaiacol glycerin evenly, and add water to make a plastic soft material.

(2) The soft material is extruded and rounded by the extrusion and rounding device. Process: Extrusion speed is about 75rpm, spheronization speed is 900-1000rpm, and then dried at 60°C, screened and coated with 16-24 mesh loaded pill core.

II. Sustained-release coating process: use a fluidized bed device to coat the sustained-release coating layer

The above-mentioned drug-loaded pellet cores were placed in a miniGlatt coating device, a coating solution was prepared according to the coating prescription, and diluted with water to a concentration of 15%, the peristaltic pump was turned on, and the coating solution was slowly sprayed into the fluidized bed.

Material bed temperature: 30～35℃ Feed temperature: 50～60℃ Air pressure: 2.0bar

III. Immediate release coating process

Turn on the peristaltic pump and spray the guaiacol/HPMC aqueous solution into the fluidized bed

Material bed temperature: 30～35℃ Feed speed: 50～60℃ Air pressure: 2.0bar

After coating the pellets in the fluidized bed, continue to dry for 15 minutes, transfer to a 40°C oven, and dry for 8 hours to make the coating film heal completely.

Example 2

Pill Loaded Prescription:

Guaifenesin 100g

Microcrystalline Cellulose 96g

Povidone 4g

Extended Release Coating Prescription:

Surelease 16g

Immediate Release Coating Prescription:

Guaifenesin 25g

Povidone 2.5g

The preparation process is as in Example 1.

Example 3

Pill Loaded Prescription:

Guaifenesin 160g

Microcrystalline Cellulose 38g

Sodium Carboxymethyl Cellulose 2g

Extended Release Coating Prescription:

Surelease 32g

Hydroxypropyl methylcellulose 0.8g

Immediate Release Coating Prescription:

Guaifenesin 17.8g

Hydroxypropyl Cellulose 1.78g

The preparation process is as in Example 1.

Example 4

Pill Loaded Prescription:

Guaifenesin 140g

Microcrystalline Cellulose 56g

Hydroxypropyl Cellulose 4g

Extended Release Coating Prescription:

Surelease 64g

Hydroxypropyl Methyl Cellulose 2.4g

Immediate Release Coating Prescription:

Guaifenesin 35g

Sodium carboxymethylcellulose 3.5g

The preparation process is as in Example 1.

Example 5

Pill Loaded Prescription:

Guaifenesin 120g

Microcrystalline Cellulose 77g

Hydroxypropyl Methyl Cellulose 3g

Extended Release Coating Prescription:

Surelease 48g

Hydroxypropyl Methyl Cellulose 1.2g

Immediate Release Coating Prescription:

Guaifenesin 21.2g

Hydroxypropyl Methyl Cellulose 2.1g

The preparation process is as in Example 1.

Embodiment 6-9

The drug-loaded pill core and the quick-release coating process are the same as in Example 1, except that polyacrylic acid resin series materials are used in the slow-release coating layer, and the prescription is as follows:

Example 6 7 8 9 Eudragit NE30D 13.3g 66.7g 26.7g 53.3g Propyl Methyl Cellulose / 4g 0.4g 1.6g Talc powder 2g 10g 4g 8g water 15g 70g 27g 53g

(The above is the sustained-release coating prescription)

Examples 10-13

The drug-loaded pill core and the quick-release coating process are the same as in Example 1, except that polyacrylic acid resin series materials are used in the slow-release coating layer, and the prescription is as follows:

Example 14

(Homemade pellets and American double-layer tablets The comparative example of drug release in vitro)

Method: According to the method 1 in the second method of the second method of the dissolution measurement method of the Chinese Pharmacopoeia 2005 edition, the device of the first method of the dissolution measurement method is used, and the rotation speed is 100 rpm. Samples are taken on time, and measured, and the release rate is calculated. The results are shown in The following table.

Release rate:

Claims (5)

1. Guaiacol glycerin ether sustained-release pellets, characterized in that the pellets are composed of drug-loaded pellet cores, sustained-release coatings and immediate-release drugs loaded with effective therapeutic doses of active ingredients and pharmaceutical adjuvants from the inside to the outside. layer composition; in the drug-loaded ball core, the active ingredient is guaiacol glyceryl ether, and its content is 50% to 90% of the weight of the drug-loaded ball core; pharmaceutical excipients include microcrystalline cellulose, hydroxypropyl methylcellulose One or a mixture of polyvinyl alcohol, povidone, hydroxypropyl cellulose or sodium carboxymethyl cellulose, the amount of which is 10% to 50% of the weight of the drug-loaded pellet core; The sustained-release coating layer is ethyl cellulose series polymer or polyacrylic acid resin series polymer, and its addition amount is 2% to 10% of the weight of the drug-loaded pellet core; In the described sustained-release coat layer, the polyacrylic acid resin series polymer comprises polyacrylic acid resin, porogen and plasticizer, and described porogen is selected from low-viscosity hydroxypropyl methylcellulose, polyethylene glycol Or one of povidone or its mixture, and the plasticizer is selected from one of triethyl citrate, dibutyl sebacate or triacetin or its mixture; The immediate-release drug layer is composed of guaiacol glyceryl ether and one or a mixture selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose or povidone, The amount of this layer is 10%-20% of the total drug amount of the pellets. 2. The guaiacol sustained-release pellets according to claim 1, characterized in that, in the drug-loaded pellet core, the pharmaceutical excipient is microcrystalline cellulose. 3. according to the guaiacol sustained-release pellet of claim 1, it is characterized in that, in described sustained-release coat layer, ethylcellulose series polymer comprises ethylcellulose and porogen, and described The porogen is selected from one of low-viscosity hydroxypropyl methylcellulose, polyethylene glycol or povidone, or a mixture thereof. 4. The preparation method of the guaiacol glycerin ether sustained-release pellets described in any one of claims 1 to 3, characterized in that it comprises the following steps: (1) After the calculated amount of medicine is mixed with pharmaceutical excipients, a binder is added to make a soft material, and the soft material is made into a drug-loaded pill core through an extrusion device; (2) The drug-loaded pill core is coated with a slow-release coating layer by the pot-packing method or fluidized bed technology to obtain a slow-release drug-loaded pellet; (3) Slow-release drug-loaded pellets are coated with an immediate-release drug layer in a coating device, dried to allow the coating to heal, and then sieved to obtain the guaiacol sustained-release pellets. 5. preparation method according to claim 4, wherein the binding agent described in step (1) is hydroxypropyl methylcellulose, povidone, hydroxypropylcellulose or sodium carboxymethylcellulose aqueous solution one or a mixture thereof.