CN101933913A - Dexmethylphenidate hydrochloride dual-release preparation and preparation method thereof - Google Patents

Abstract

The invention belongs to the field of medicine, and in particular relates to a dexmethylphenidate hydrochloride dual-release preparation and a preparation method thereof. The preparation of the invention comprises pellets with different release performance, wherein the pellets comprise 10 to 70 percent of quick-response pellets and 20 to 60 percent of enteric-coated pellets based on the total weight of the pellets. The release mode in the preparation can achieve an ideal treatment effect and ensure that the medicament concentration in blood plasma in vivo is maintained as long as 16 to 24 hours. Compared with a dexmethylphenidate hydrochloride common preparation which is taken twice per day, the dual-release preparation can reduce a peak value of the medicament concentration in the blood plasma in vivo after the medicament is taken for the second time, and simultaneously the bioavailability of the medicament is not influenced. The dexmethylphenidate hydrochloride adopted by the invention can effectively reduce toxic and side effects brought by a racemic compound and improve a treatment effect and the medication compliance of a patient.

Description

Dexmethylphenidate hydrochloride double-release preparation and preparation method thereof

Technical Field

The invention relates to a preparation method of a pharmaceutical preparation in the field of pharmacy, in particular to a dexmethylphenidate hydrochloride double-release capsule preparation and a preparation method thereof.

Technical Field

Dexmethylphenidate hydrochloride is the racemic d-threo enantiomer of methylphenidate hydrochloride and is a central nervous system stimulant. The chemical name is (R, R) - (+) -alpha-phenyl-2-piperidine acetic acid methyl ester hydrochloride. It has a molecular formula: c₁₄H₁₉NO₂HCl. Molecular weight is 269.77, and structural formula is:

the methylphenidate hydrochloride is a first-line medicine for treating Attention Deficit Hyperactivity Disorder (ADHD), belongs to a relatively safe and effective medicine, and has an effective rate of 78-80%. ADHD is the most common mental development disorder in childhood. The main symptoms of the disease are: attention deficit, behavior impulsion, easy distraction, and hyperactivity, often accompanied by learning difficulties and conduct impairment. The investigation shows that the prevalence rate of the disease in domestic children is 1.5-10%, and the actual incidence rate is higher because the disease cannot be paid enough attention for a long time.

However, the methylphenidate hydrochloride is found to have obvious side effects in clinical medication, and the following symptoms are frequently found: including headache, abdominal pain, insomnia, and poor appetite. Common formulations of methylphenidate require two to three times daily due to their short half-life, are prone to patient missed medication, poor compliance, and can lead to drug addiction and dependence beyond therapeutic doses.

Disclosure of Invention

The invention provides a preparation method of a double-release capsule preparation taking dexmethylphenidate hydrochloride as a main drug, aiming at reducing the toxic and side effects of the methylphenidate hydrochloride so as to be used for the long-term treatment of patients.

The invention also aims to overcome the central nervous side effect caused by the higher peak value of the second blood concentration caused by twice-daily administration of the common preparation, improve the administration compliance and reduce the possibility of poor curative effect of a patient due to missed administration of the medicine.

The technical scheme adopted by the invention is as follows:

the dexmethylphenidate hydrochloride double-release capsule has the performance of releasing the medicine twice, comprises a quick-release pellet part and a delayed-release pellet part, and is prepared from dexmethylphenidate hydrochloride, a filling agent, a disintegrating agent, an adhesive, an isolation coating material, a plasticizer and a pore-forming agent.

Wherein,

(a) the pellet cores of the quick-release pellet and the delayed-release pellet are the same, the drug-carrying pellet is prepared by adding the adhesive and the disintegrating agent into the mixture of the dextromethorphan hydrochloride and the filling agent which comprises one or more of sucrose, lactose, microcrystalline cellulose, algal polysaccharide and chitosan, and then extruding and rounding, and the diameter of the obtained pellet can be controlled within 0.3-1.5mm, preferably within the range of 1.0 +/-0.1 mm, and the pellet core is used for preparing the quick-release pellet or the delayed-release pellet.

(b) The quick-release pellet is prepared by selecting one or more isolation coating materials from the drug-loaded pellet under certain process conditions, wherein the isolation coating materials are selected from the following materials: one or more of Opadry I, Opadry II, Opadry AMB, Opadry MP, hydroxypropyl methylcellulose and polyvinyl alcohol. The prepared pellet has smooth and round surface, and good stability and fluidity.

(c) The delayed release pellet is coated with fast release pellet and the coating material includes one or several of ethyl cellulose, hydroxypropyl methyl cellulose, polyacrylic resin, ethyl cellulose water dispersion, hydroxypropyl cellulose, hydroxyethyl cellulose acetate, cellulose acetate phthalate, vinyl acetate phthalate and hydroxypropyl methyl cellulose phthalate, and pore creating agent and plasticizer are also added to raise the stability of the enteric coating.

Therefore, the quick-release pellet part in the dexmethylphenidate hydrochloride double-release capsule comprises the following components in percentage by weight:

the quick-release pellet comprises the following components:

2 to 30 percent of dexmethylphenidate hydrochloride

5 to 95 percent of filling agent

0 to 10 percent of disintegrating agent

0.5 to 15 percent of adhesive

0 to 10 percent of isolation clothes material

The delayed-release pellet part comprises the following components in percentage by weight:

2 to 25 percent of dexmethylphenidate hydrochloride

0.3 to 10 percent of adhesive

50 to 88 percent of filling agent

0 to 9 percent of disintegrating agent

0 to 9 percent of isolation clothes material

30 to 68 percent of coating material

1 to 8 percent of plasticizer

1 to 8 percent of pore-foaming agent

Wherein the quick-release pellet part is a skeleton type pellet, and the main medicine is dexmethylphenidate hydrochloride.

The filler can be one or more of lactose, microcrystalline cellulose, starch, and dextrin, preferably microcrystalline cellulose.

The adhesive can be one or more selected from water, anhydrous ethanol, mixed solution of water and ethanol, hydroxypropyl methylcellulose solution, and hydroxypropyl cellulose solution.

The disintegrating agent can be one or more of sodium carboxymethyl starch, crospovidone, sodium carboxymethyl cellulose, and starch slurry.

The isolation coat material can be selected from one or more of Opadry I, Opadry II, Opadry MP, hydroxypropyl methylcellulose, ethyl cellulose, and methylcellulose.

Wherein the delayed release pellet fraction:

the filler can be one or more of lactose, starch, microcrystalline cellulose, pregelatinized starch, mannitol, chitosan, and dextrin, preferably microcrystalline cellulose.

The adhesive can be one or more selected from water, anhydrous ethanol, mixed solution of water and ethanol, hydroxypropyl methylcellulose solution, and hydroxypropyl cellulose solution.

The disintegrating agent can be one or more of sodium carboxymethyl starch, crospovidone, sodium carboxymethyl cellulose, and starch slurry.

The isolation coating material can be selected from one or more of Opadry, Opadry MP, hypromellose, and polyvinyl alcohol.

The coating material can be one or more of ethyl cellulose, hypromellose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, methacrylic resin, polylactic acid, and palm wax.

The plasticizer can be diethyl phthalate, dibutyl sebacate glyceryl stearate, triethyl citrate, tributyl citrate, diethyl succinate, and rectified coconut oil.

The pore-forming agent can be one or more of polyethylene glycol, pulvis Talci, hydroxypropyl methylcellulose, and polyvidone.

The dexmethylphenidate hydrochloride double-release capsule is in a pellet form filled into a pellet in the capsule, wherein the pellet comprises a pellet core and a coating, and the preparation method of the pellet core comprises the following steps:

pulverizing the medicine, filler and disintegrant into a certain particle size range, sieving with 80-100 mesh sieve, mixing in stirring mixer, adding adhesive, making into soft material, and making into medicine-carrying pellet with uniform particle size by extrusion and rolling method, wherein the pellet particle size can be controlled within the range of 0.6-1.2 mm according to the length of the cylinder formed by extrusion, and preferably controlled at 1.0 + -0.1 mm.

The invention relates to a dexmethylphenidate hydrochloride double-release capsule, which comprises the following coating methods:

the preferable coating material is coated by a fluidized bed or a coating pan, the coating material is atomized under a proper pressure and then sprayed into the fluidized bed, and the coating material forms a coating film and is attached to the pellets at a certain temperature. The pellet can obtain the drug-carrying pellet with uniform coating at a certain fluidization speed. After the pellets are placed at a certain temperature, the stability of the coating can be improved, and the influence of the pellets on external environmental factors such as illumination, high temperature and humidity can be reduced.

Compared with the total feeding amount, the yield of the obtained pellets is 90-100% by adopting an extrusion spheronization method, and the loss of the dexmethylphenidate hydrochloride raw material medicine in the preparation process can be reduced compared with a laminated medicine feeding method. After the obtained pellets are filled into capsules, the release performance is stable and uniform, three batches are selected for in vitro release degree experimental determination, and the relative standard error of the batch release degree is less than 3%.

The dexmethylphenidate hydrochloride double-release capsule of the invention contains quick-release pellets and delayed-release pellets with the mass ratio of 3: 1 to 1: 3, and the preferred mass ratio is as follows: 358: 431.

The effective dose of the dexmethylphenidate hydrochloride in the dual-release preparation is 5-40mg, preferably 5-20mg, so that the dexmethylphenidate hydrochloride dual-release capsule is suitable for people with different weights, and has similar or same in-vivo pharmacokinetic characteristics when different specifications correspond to different people.

The dexmethylphenidate hydrochloride double-release capsule of the invention has the advantages that the weight proportion of the quick-release pellets is 30-60%, and the weight proportion of the delayed-release pellets is 40-60%.

Compared with racemic methylphenidate, the dexmethylphenidate hydrochloride has better treatment effect and smaller side effect. The probability of occurrence of side effects of the conventional dexmethylphenidate formulation is about 7.3% as shown in US 6355656B 1, whereas the probability of occurrence of side effects of the dual dexmethylphenidate formulation is only 1.3%.

The improvement of the dexmethylphenidate hydrochloride double-release preparation provided by the invention has the advantages that the human body tests that the dexmethylphenidate hydrochloride double-release preparation taken once a day can generate two times of drug release, the treatment effect is equivalent to that of a common preparation taken twice each time, the peak value of plasma drug concentration can be stably controlled, the side effect and addiction brought by the drug are reduced, and the bioavailability of the drug is improved to ensure the treatment effect. After the pellets are filled into capsules, the release performance is stable and uniform according to the requirement of preparation stability, and the relative standard error of the batch release degree is less than 3%.

According to the dexmethylphenidate hydrochloride double-release preparation provided by the invention, the disintegrant is added into the drug-loaded pellet core, so that the release of the drug in the quick-release pellet after the drug is taken is accelerated, and the time required for complete dissolution of the drug is reduced; the dexmethylphenidate hydrochloride double-release preparation provided by the invention has the advantages that the quick-release part is released in a short time, the plasma drug concentration reaches a first peak value, the drug starts to be released for the second time after about 2.5 hours, a second plasma drug concentration peak value is generated, the concentrations of the two peak values are similar, the toxic and side effects and addiction caused by the fact that the drug concentration exceeds a treatment window are reduced, and the dexmethylphenidate hydrochloride double-release preparation is taken once every ten am.

The following experimental data illustrate the beneficial effects of the present invention: the capsules prepared in example 1 were used for experiments, and conventional drug stability studies have shown that the preferred formulations of the present invention have extremely high stability and unexpected technical effects compared to the existing products and the prior art.

TABLE 1 stability Studies of dexmethylphenidate hydrochloride dual release formulations under high heat conditions

TABLE 2 stability Studies of dexmethylphenidate hydrochloride dual release formulations under high humidity conditions

TABLE 3 stability study of dexmethylphenidate hydrochloride dual release formulations under high light irradiation

Release tests for the invention:

releasing the sample in 0.01mol/L hydrochloric acid solution for 0-2 hours, then transferring the sample to release solution of phosphate buffer solution (pH6.8) for 2-10 hours, and releasing the sample, wherein the volume of the medium is 500 ml; the apparatus used in the first dissolution method was set at 100 rpm.

The results show that: the dexmethylphenidate hydrochloride dual-release preparation achieves 50% of accumulative release rate in acid within 2 hours and 99.67% of accumulative release rate in buffer solution with pH6.8 within 2 hours.

The invention has the advantages that:

(1) the preparation process of the dexmethylphenidate hydrochloride capsule is simple and easy to implement, 10000-30000 units of scale production can be completed in laboratory scale by adopting a low-temperature extrusion spheronizer and a fluidized bed, the production efficiency is high, and 5-40mg of dexmethylphenidate hydrochloride capsules with different specifications can be prepared;

(2) the double-release preparation is equivalent to the bioavailability of a common preparation through the pharmacokinetics research in an animal, does not generate the problem of reducing the bioavailability due to partial delayed release, reduces the second plasma drug concentration peak value and the possibility of generating side effects by a double-release model, and improves the medication compliance of patients after once daily administration.

(3) The preparation of the dexmethylphenidate hydrochloride of the invention has stable properties, controllable drug content and related substances within 3 months through accelerated test investigation, and is suitable for industrial production.

Drawings

FIG. 1 shows the in vitro release rates of three batches of dexmethylphenidate hydrochloride double release formulations obtained by the preferred formulation

Detailed Description

The following are specific embodiments of the present invention, which are intended to further illustrate the invention and not to limit it. All technical solutions equivalent to the present invention belong to the protection scope of the present invention.

Example 1

Prescription

(1) Pellet core

Microcrystalline cellulose 49g

Dexpipristal hydrochloride 5.0g

Carboxymethyl cellulose 1g

44ml of 2% hydroxypropylmethylcellulose solution

(2) Quick-release pellet

Pellet core 56g

6% hydroxypropyl methylcellulose solution 11.2ml

(3) Delayed release pellet

Pellet core 100g

Ethyl cellulose aqueous dispersion 33.3ml of 15% solids content

Dibutyl phthalate 0.2g

Talcum powder 1.6g

The preparation process comprises the following steps:

(1) process for preparing pellet core

Pulverizing the medicine, filler and disintegrant into a certain particle size range, sieving with 80 mesh sieve, mixing in a stirring mixer for 1h, adding 44ml of 2% (w/v) hydroxypropyl methylcellulose solution, and making into soft material. Opening a low-temperature refrigerator, controlling the temperature at 4-15 ℃, placing the soft material into a low-temperature high-pressure extruder to pass through sieve holes after 10min, selecting sieve plates with the diameter of 0.9-1.0mm for the sieve holes, adjusting the extrusion speed to 40rpm to form a cylindrical soft material with moderate length, rounding the soft material in a rounding machine at the speed of 2000rpm for 9min to form drug-loaded pellets with uniform particle size, wherein the particle size of the pellets can be controlled within the range of 0.6-1.2 mm according to the length of a sheared cylinder. Taking the yield of the coating process as an evaluation index, preferably coating pellets with the particle size of 1.0 +/-0.1 mm, drying in an oven at 40 ℃ for 45min, checking the uniformity and the water content of the pellets with a 16-24-mesh sieve, and taking the pellets as pellet cores for standby after the pellets are qualified.

(2) Preparation process and technology of quick-release pellets

Putting 56g of pellet core of the drug-loaded pellet into a fluidized bed, adjusting the temperature of inlet air to 45 ℃, and adjusting the inlet air volume to 50m³About/h, using the prepared 6% hydroxypropyl methylcellulose aqueous solution as a barrier coating material) is firstly added into an atomizing chamber at a pump speed of 1.5ml/min through bottom spraying by a peristaltic pump to perform atomizing coating under an atomizing pressure of 2bar, the pumping speed is gradually increased to 6ml/min until the coating solution is coated, and the pellets are continuously fluidized and dried in a fluidized bed for 30min after the coating is finished, thus obtaining the quick-release pellets.

(3) Delayed release pellet preparation process

Placing the quick-release pellets in a fluidized bed, adjusting the fluidization temperature to 45 deg.C, and the dry air flow rate to 50m³And h, taking the ethyl cellulose aqueous dispersion, adding water to dilute the ethyl cellulose aqueous dispersion into a suspension with the solid content of 15%, adding a prescribed amount of talcum powder and triethyl citrate, pumping the suspension into an atomizing chamber for atomizing coating (the atomizing pressure is 2bar) by using a peristaltic pump in a bottom spraying mode at 1.5ml/min, gradually increasing the pumping speed to 7ml/min until the coating liquid is completely coated, continuously fluidizing and drying the suspension in a fluidized bed for 30min, taking the suspension out, curing the suspension at 45 ℃ for 10h, selecting and sieving a pellet with a 16-24-mesh sieve, checking the character and the release degree, and obtaining the delayed release pellet after the pellet is qualified.

(4) Filling of dexmethylphenidate hydrochloride delayed-release capsules

The quick-release pellets and the delayed-release pellets are respectively filled into capsules according to the weight ratio of 30: 43, and then the finished product of the dexmethylphenidate hydrochloride capsule is obtained.

Example 2

Prescription

(1) Pellet core

Microcrystalline cellulose 49g

Dexpipristal hydrochloride 5.0g

0.9g crospovidone

44ml of 2% hydroxypropylmethylcellulose solution

(2) Quick-release pellet

Pellet core 56g

11.2ml of 20% Opadry I aqueous solution

(3) Delayed release pellet

Pellet core 250g

Eudragit L30D-55166.7 g

12.5g triethyl citrate

Talcum powder 12.5g

216ml of water

The preparation process comprises the following steps:

(1) process for preparing pellet core

Pulverizing the medicinal materials, filler and disintegrant into a certain particle size range, sieving with 80 mesh sieve, mixing in a stirring mixer for 1 hr, adding 44ml hydroxypropyl methylcellulose solution, and making into soft material. Opening a low-temperature refrigerator, controlling the temperature at 4-15 ℃, putting the soft material into a low-temperature high-pressure extruder to pass through sieve holes after 10min, selecting sieve plates with the diameter of 0.9-1.0mm for the sieve holes, adjusting the extrusion speed to 40rpm to form a cylindrical soft material with proper length, rounding the soft material in a rounding machine at the speed of 2000rpm for 9min to form drug-loaded pellets with uniform particle size, controlling the pellet size to be in the range of 0.6-1.2 according to the length of a sheared cylinder, preferably controlling the particle size to be 1.0 +/-0.1 mm, placing the pellets in an oven for drying at 40 ℃ for 45min, checking the uniformity and the water content of the pellets with the diameter of 16-24 meshes, and using the pellets as pellet cores for standby application.

(2) Preparation process and technology of quick-release pellets

Putting 56g of pellet core of the drug-loaded pellet into a fluidized bed, adjusting the temperature of inlet air to 45 ℃, and adjusting the inlet air volume to 50m³About/h, using the prepared Opadry I solution as a barrier coating material) is firstly added into an atomizing chamber at a pump speed of 1.5ml/min through bottom spraying by a peristaltic pump, the atomizing pressure is 2bar, the pumping speed is gradually increased to 6ml/min until the coating liquid is coated, and the pellets are continuously fluidized and dried in a fluidized bed for 30min after the coating is finished, thus obtaining the quick-release pellets.

(3) Delayed release pellet preparation process

Placing the quick-release pellets in a fluidized bed, adjusting the fluidization temperature to 45 deg.C, and the dry air flow rate to 50m³And/h, adding 166.7g of enteric-coated film coating material Utex L30D-55 into 50ml of water, adding talcum powder and triethyl citrate into 166ml of aqueous solution, homogenizing for 5 minutes at 10000rpm by using a high-shear homogenizer, mixing and stirring the talcum powder and the triethyl citrate for 30 minutes, pumping the mixture into an atomizing chamber for atomizing and coating by using a peristaltic pump in a bottom spraying mode at 1.5ml/min (the atomizing pressure is 2bar), gradually increasing the pumping rate to 7ml/min until the coating liquid is completely coated, continuously performing fluidized drying in a fluidized bed for 30 minutes, taking out, curing for 10 hours at 45 ℃, selecting and screening a 16-24-mesh small pill, checking the property release degree, and obtaining the delayed-release small pill after the product is qualified.

(4) Filling of dexmethylphenidate hydrochloride delayed-release capsules

The quick-release pellets and the delayed-release pellets are respectively filled into capsules according to the weight ratio of 30: 43, and then the finished product of the dexmethylphenidate hydrochloride capsule is obtained.

Example 3

Prescription

(1) Pellet core

Microcrystalline cellulose 49g

Dexpipristal hydrochloride 5.0g

0.5g of polyvidone

44ml of 2% hydroxypropylmethylcellulose solution

(2) Quick-release pellet

Pellet core 56g

11.2ml of 20% Opadry MP solution

(3) Delayed release pellet

Pellet core 100g

Aqueous ethylcellulose dispersion 33.33ml with a solids content of 15%

The preparation process comprises the following steps:

(1) process for preparing pellet core

Pulverizing the medicinal materials, filler and disintegrant into a certain particle size range, sieving with 80 mesh sieve, mixing in a stirring mixer for 1 hr, adding 44ml hydroxypropyl methylcellulose solution, and making into soft material. Opening a low-temperature refrigerator, controlling the temperature at 4-15 ℃, putting the soft material into a low-temperature high-pressure extruder after 10min to pass through sieve holes, selecting sieve plates with the diameter of 0.9-1.0mm from the sieve holes, adjusting the extrusion speed to 40rpm to form a cylindrical soft material with proper length, rolling the cylindrical soft material in a rolling machine at the speed of 2000rpm for 9min to form drug-loaded pellets with uniform particle size, controlling the pellet size to be in the range of 0.6-1.2 according to the length of a sheared cylinder, preferably controlling the particle size to be 1.0 +/-0.1 mm, placing the pellets in an oven for drying at 40 ℃ for 45min, checking the water content and the mass content of the pellets with the diameter of 16-24 meshes, and using the pellets as pellet cores for standby after the pellets are qualified.

(2) Preparation process and technology of quick-release pellets

Putting 56g of pellet core of the drug-loaded pellet into a fluidized bed, adjusting the temperature of inlet air to 45 ℃, and adjusting the inlet air volume to 50m³About/h, adding the prepared 20% solid content Opadry MP water solution) into an atomizing chamber at a pump speed of 1.5ml/min by a peristaltic pump through bottom spraying, atomizing at a pressure of 2bar, gradually increasing the pumping speed to 6ml/min until coating liquid is completely coated, and continuously fluidizing and drying the pellets in a fluidized bed for 30min after coating is finished to obtain the quick-release pellets.

(3) Delayed release pellet preparation process

Placing the quick-release pellets in a fluidized bed, adjusting the fluidization temperature to 45 deg.C, and the dry air flow rate to 50m³And h, adding 90% ethanol into the enteric-coated film coating material to prepare a 15% aqueous dispersion solution, pumping into an atomizing chamber for atomizing coating (the atomizing pressure is 2bar) by a peristaltic pump in a bottom spraying mode at 1.5ml/min, gradually increasing the pumping speed to 7ml/min until the coating solution is completely coated, continuously fluidizing and drying in a fluidized bed for 30 minutes, taking out, curing at 45 ℃ for 10 hours, selecting pellets of a 16-24-mesh sieve, checking the character release degree, and obtaining the delayed-release pellets after the qualified product.

(4) Filling of dexmethylphenidate hydrochloride delayed-release capsules

The quick-release pellets and the delayed-release pellets are respectively filled into capsules according to the weight ratio of 40: 43, and then the finished product of the dexmethylphenidate hydrochloride capsule is obtained.

Example 4

Prescription

(1) Pellet core

Microcrystalline cellulose 49g

Dexpipristal hydrochloride 5.0g

Carboxymethyl cellulose 1g

44ml of 2% hydroxypropylmethylcellulose solution

(2) Quick-release pellet

Pellet core 56g

20% Opadry II 14ml

(3) Delayed release pellet

Pellet core 100g

Hydroxypropyl methylcellulose phthalate HP-5515 g

Polyethylene glycol 60001.5 g

80% ethanol solution 150ml

The preparation process comprises the following steps:

(1) process for preparing pellet core

Pulverizing the medicinal materials, filler and disintegrant into a certain particle size range, sieving with 80 mesh sieve, mixing in a stirring mixer for 1 hr, adding 44ml hydroxypropyl methylcellulose solution, and making into soft material. Opening a low-temperature refrigerator, controlling the temperature at 4-15 ℃, putting the soft material into a low-temperature high-pressure extruder after 10min to pass through sieve holes, selecting sieve plates with the diameter of 0.9-1.0mm from the sieve holes, adjusting the extrusion speed to 40rpm to form a cylindrical soft material with proper length, rolling the cylindrical soft material in a rolling machine at the speed of 2000rpm for 9min to form drug-loaded pellets with uniform particle size, controlling the pellet size to be in the range of 0.6-1.2 according to the length of a sheared cylinder, preferably controlling the particle size to be 1.0 +/-0.1 mm, placing the pellets in an oven for drying at 40 ℃ for 45min, checking the water content and the mass content of the pellets with the diameter of 16-24 meshes, and using the pellets as pellet cores for standby after the pellets are qualified.

(2) Preparation process and technology of quick-release pellets

Putting 56g of pellet core of the drug-loaded pellet into a fluidized bed, adjusting the temperature of inlet air to 45 ℃, and adjusting the inlet air volume to 50m³About/h, adding the prepared 20% Opadry II aqueous solution) into an atomizing chamber at a pump speed of 1.5ml/min through bottom spraying by a peristaltic pump to perform atomizing coating at an atomizing pressure of 2bar, gradually increasing the pumping speed to 6ml/min until the coating solution is completely coated, and continuously performing fluidized drying on the pellets in a fluidized bed for 30min after the coating is finished to obtain the quick-release pellets.

(3) Delayed release pellet preparation process

Placing the quick-release pellets in a fluidized bed, adjusting the fluidization temperature to 40 deg.C, and drying air flow rate to 50m³And h, dissolving 15g of enteric hydroxypropyl methylcellulose phthalate HP-55 in 150ml of 80% ethanol, adding 1.5g of polyethylene glycol 6000, pumping into an atomizing chamber for atomizing and coating (the atomizing pressure is 2bar) by a peristaltic pump in a bottom spraying mode at 1.5ml/min, gradually increasing the pumping speed to 7ml/min until the coating liquid is completely coated, continuously fluidizing and drying in a fluidized bed for 30 minutes, taking out, curing at 45 ℃ for 10 hours, selecting pellets screened by a 16-24-mesh sieve, checking the property release degree, and obtaining the delayed release pellets after the pellets are qualified.

(4) Filling of dexmethylphenidate hydrochloride delayed-release capsules

The quick-release pellets and the delayed-release pellets are respectively filled into capsules according to the weight ratio of 30: 43, and then the finished product of the dexmethylphenidate hydrochloride capsule is obtained.

Experimental example 1:

the pellet prepared in example 1 was used as a test sample, and the release rate test method was as follows:

taking the product, according to a dissolution rate measuring method (second method (2) of appendix X D of second part of Chinese pharmacopoeia 2005 edition), adopting a dissolution rate measuring method (second method of appendix X C of second part of Chinese pharmacopoeia 2005 edition) device, taking 500ml of 0.1mol/L hydrochloric acid solution as a solvent, rotating at 50 revolutions per minute, operating according to the method, taking a proper amount of solution after 2 hours, filtering, and taking the subsequent filtrate as a test solution (1). Discarding the acid solution in each container, immediately adding 500ml of phosphate buffer solution preheated to 37 deg.C and pH 7.4, rotating at constant speed, collecting appropriate amount of solution after 45min, and filtering to obtain filtrate as sample solution (2). Measuring the amount of the traditional Chinese medicine in the test solution by high performance liquid chromatography, precisely measuring the reference solution and the test solution, respectively injecting into a liquid chromatograph, recording chromatogram, and calculating the release amount at different times according to an external standard method.

The experimental results are shown in the attached drawings, and the experimental results of the examples 2, 3 and 4 are the same as those of the example 1 under the same test conditions and meet the requirements.

Claims (10)

1. A dual-release dexmethylphenidate hydrochloride capsule for releasing medicine twice is composed of the quick-release micropill and the delayed-release micropill, and is prepared from dexmethylphenidate hydrochloride, filler, disintegrant, adhesive, isolating coating, plasticizer and pore-forming agent.

2. The dual release capsule of claim 1, wherein the immediate release pellet fraction comprises the following components in weight percent:

2 to 30 percent of dexmethylphenidate hydrochloride

5 to 95 percent of filling agent

0 to 10 percent of disintegrating agent

0.5 to 15 percent of adhesive

0-10% of isolation clothes material.

3. The dual release capsule of claim 1, wherein the delayed release pellet fraction comprises the following components in weight percent:

2 to 25 percent of dexmethylphenidate hydrochloride

0.3 to 10 percent of adhesive

50 to 88 percent of filling agent

0 to 9 percent of disintegrating agent

0 to 9 percent of isolation clothes material

30 to 68 percent of coating material

1 to 8 percent of plasticizer

1-8% of pore-foaming agent.

4. The dual release capsule of claim 1, wherein:

the pellet is a skeleton type pellet, the main drug is dexmethylphenidate hydrochloride,

the filler of the quick-release pellet can be one or more of lactose, microcrystalline cellulose, starch and dextrin,

the disintegrating agent of the quick release pellet can be one or more of sodium carboxymethyl starch, crospovidone, sodium carboxymethyl cellulose and starch slurry,

the adhesive of the quick-release pellet can be one or more of water, absolute ethyl alcohol, a mixed solution of water and ethyl alcohol, a hydroxypropyl methyl cellulose solution and a hydroxypropyl cellulose solution,

the isolation coating material of the quick-release pellet can be selected from one or more of Opadry I, Opadry II, Opadry MP, hydroxypropyl methylcellulose, ethyl cellulose and methylcellulose,

the filler of the delayed-release pellet can be selected from one or more of the following auxiliary materials: lactose, starch, microcrystalline cellulose, pregelatinized starch, mannitol, chitosan, dextrin,

the disintegrating agent of the delayed release pellet can be one or more of sodium carboxymethyl starch, crospovidone, sodium carboxymethyl cellulose and starch slurry,

the adhesive of the quick-release pellet can be one or more of water, absolute ethyl alcohol, a mixed solution of water and ethyl alcohol, a hydroxypropyl methyl cellulose solution and a hydroxypropyl cellulose solution,

the isolation coating material of the delayed-release pellet can be one or more of Opadry, Opadry MP, hypromellose and polyvinyl alcohol,

the enteric material of the delayed-release pellet can be one or more of ethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, methacrylic acid resin, hydroxypropyl methylcellulose phthalate and palm wax,

the delayed release pellet plasticizer can be selected from diethyl phthalate, dibutyl sebacate glyceryl stearate, triethyl citrate, tributyl citrate, diethyl succinate, and rectified coconut oil,

the delayed release pellet pore-forming agent can be one or more of polyethylene glycol, talcum powder, hydroxypropyl methylcellulose and polyvidone.

5. The dual release capsule of claim 1, wherein the effective amount of dexmethylphenidate hcl is between 5-40mg, preferably 5-20mg, to accommodate use by people of different body weight, and different specifications have similar or identical in vivo pharmacokinetic profiles for different people.

6. The dual release capsule of claim 1, wherein the fast-releasing pellets are present in an amount of 30-60% by weight and the delayed-releasing pellets are present in an amount of 40-60% by weight.

7. The dual release capsule of claim 1, wherein: the mass ratio of the quick-release pellets to the delayed-release pellets contained in the capsule is between 3: 1 and 1: 3, and the preferred mass ratio is as follows: 358: 431.

8. The dual release capsule according to claim 1, consisting of:

(1) pellet core

Microcrystalline cellulose 49g

Dexpipristal hydrochloride 5.0g

Carboxymethyl cellulose 1g

44ml of 2% hydroxypropylmethylcellulose solution

(2) Quick-release pellet

Pellet core 56g

6% hydroxypropyl methylcellulose solution 11.2ml

(3) Delayed release pellet

Pellet core 100g

Ethyl cellulose aqueous dispersion 33.3ml of 15% solids content

Dibutyl phthalate 0.2g

1.6g of talcum powder.

9. The dual release capsule according to claim 1, consisting of:

(1) pellet core

Microcrystalline cellulose 49g

0.9g crospovidone

44ml of 2% hydroxypropylmethylcellulose solution

(2) Quick-release pellet

Pellet core 56g

11.2ml of 20% Opadry I aqueous solution

(3) Delayed release pellet

Pellet core 250g

Eudragit L30D-55166.7 g

12.5g triethyl citrate

Talcum powder 12.5g

216ml of water.

10. The method for preparing a dual release capsule according to claim 1, comprising the steps of: pulverizing the medicine, the filling agent and the disintegrating agent into a certain particle size range, passing through a 80-100 mesh screen, uniformly mixing in a stirring mixer, adding an adhesive to prepare a soft material, preparing the medicine-carrying pellets with uniform particle size by adopting an extrusion rolling method, controlling the particle size of the pellets to be in the range of 0.6-1.2 mm according to the length of a cylinder formed by extrusion, preferably controlling the particle size to be 1.0 +/-0.1 mm, coating the preferred coating material by adopting a fluidized bed or a coating pan, atomizing the coating material under a proper pressure, spraying the atomized coating material into the fluidized bed, and forming a coating film by the coating material at a certain temperature to be attached to the pellets.

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