WO2021077889A1 - Paracetamol sustained-release preparation and 3d printing preparation method therefor - Google Patents

Abstract

Disclosed are a paracetamol sustained-release preparation and a 3D printing preparation method therefor. Specifically, disclosed are a paracetamol sustained-release tablet and a method for preparing the paracetamol sustained-release tablet by using a 3D printing technology. A paracetamol sustained-release preparation, comprising the following components: 150-250 parts by weight of paracetamol; 150-350 parts by weight of a hot-melt extruded matrix; 15-35 parts by weight of a plasticizer; and 0-150 parts by weight of a disintegrating agent.

Description

Paracetamol sustained-release preparation and its 3D printing preparation method Technical field

The invention belongs to the field of medicine and preparations, and relates to a paracetamol sustained-release preparation and a 3D printing preparation method thereof. Specifically, the present invention relates to an acetaminophen sustained-release tablet, and a method for preparing the acetaminophen sustained-release tablet using 3D printing technology.

Background technique

Paracetamol (Paracetamol) is a common antipyretic and analgesic. It selectively inhibits the synthesis of prostaglandins in the hypothalamic body temperature regulation center by inhibiting cyclooxygenase, which causes peripheral blood vessels to dilate and sweat to achieve antipyretics. Its antipyretic effect is similar to that of aspirin; it has an analgesic effect by inhibiting the synthesis and release of prostaglandins, etc., and increasing the pain threshold. It is a peripheral analgesic, and its effect is weaker than that of aspirin, only mild to moderate Pain is effective. This product has no obvious anti-inflammatory effect. Acetaminophen is mainly used for fever, headache and relief of mild and moderate pain caused by colds, such as arthralgia, muscle pain, neuralgia, migraine, dysmenorrhea, cancer pain and postoperative analgesia. It can also be used for patients who are allergic, intolerant or not suitable for aspirin: such as patients with chickenpox, hemophilia and other bleeding diseases (including patients with anticoagulant therapy), as well as patients with mild peptic ulcer and gastritis. The structural formula of acetaminophen is shown in formula A below.

Tylonel is currently the only single formulation of paracetamol sustained-release tablets marketed in the United States. It is listed as a reference and standard formulation by the Orange Book of the United States, with a specification of 650 mg. The acetaminophen sustained-release tablets currently on the market in China are Tylenol and Beloxin, both of which are 650mg.

However, in 2011, the U.S. Food and Drug Administration (FDA) issued a recommendation on reducing the prescription specifications of acetaminophen, that is, each tablet should not exceed 325mg to reduce liver damage. Therefore, the currently marketed acetaminophen sustained-release tablets have larger specifications, and there is a potential risk of liver damage. Therefore, smaller specifications and need to achieve the same therapeutic purpose as acetaminophen sustained-release tablets.

Hot Melt Extrusion (HME) is a process in which materials are passed through a specific die to form a uniform shape object under elevated temperature. This technology was first used in the plastics industry. Since the 1980s, hot melt extrusion technology has begun to be applied In the pharmaceutical industry, it can solubilize insoluble drugs and mask the taste of bitter drugs, which is a good way of pharmacy. Hot melt extrusion can be divided into plunger extrusion and screw extrusion. The former extrudes the heated and melted material through a die to form it, and the latter drives the melted material to extrude it through the rotation of the screw.

Fused Deposition Modeling (FDM) printing technology is a type of 3D printing technology. This technology is to first prepare a material with a certain diameter into a wire with good printability, and then further print the wire layer by layer. The technology is simple and the equipment is streamlined. It is a good 3D printing technology. In recent years, the research of this technology in the pharmaceutical field has gradually increased. However, the preparation of the wire during the preparation process has become the difficulty of the technology. The prepared wire It must have good printing performance before it can be printed and formed by a printer. If the wire does not meet a series of requirements such as hardness and toughness, it cannot be successfully printed. This puts high requirements on the material and preparation process, which adds to the 3D printing Difficulty.

Hot melt extrusion type FDM is a combination of HME and FDM, and the drug, polymer and other auxiliary materials (such as plasticizer) are fully mixed and then heated and extruded by a hot extruder to produce a drug-containing polymer wire for 3D printing. , Can adjust the drug release characteristics by changing the shape, changing the printing polymer material and changing the printing dosage form, and improve the efficiency in the preparation of solid pharmaceutical dosage forms.

However, the necessary thermal stability of the drug in the HME-FDM combination, the necessary thermoplasticity of the polymer, and the biodegradability and other conditions limit the application range of the drug and polymer materials. The prepared pharmaceutical dosage form also has the limitation of drug loading: too low drug loading is difficult to reach the required dose; too high drug loading may affect the drug-polymer combination. In addition, the composition of the current 3D printed pharmaceutical preparations is relatively simple, mostly a binary system of drugs and polymers, and whether more other excipients can be introduced is still to be investigated and explored. The determination of the printing temperature of the material and the control of the release behavior are also difficult points in this field.

At present, it is still necessary to study acetaminophen sustained-release pharmaceutical compositions (prescriptions) suitable for 3D printing, especially suitable for the combination of HME and FDM, in order to develop new acetaminophen sustained-release preparations and their preparation methods.

Summary of the invention

After in-depth research and creative work, the inventors obtained an acetaminophen sustained-release pharmaceutical composition (prescription) suitable for 3D printing, especially suitable for the combined use of HME and FDM, and developed a new drug composition on this basis. Paracetamol sustained-release preparations (such as sustained-release tablets) and preparation methods thereof. The acetaminophen sustained-release preparation of the present invention is very suitable for preparation by 3D printing, especially 3D printing in which HME and FDM are combined, and has a good sustained-release effect. This provides the following inventions:

One aspect of the present invention relates to an acetaminophen sustained-release preparation, including the following components:

In one or more embodiments of the present invention, the paracetamol sustained-release preparation, wherein:

The hot melt extrusion matrix is selected from:

Copovidone (such as Kollidon VA64) and one or more of polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (such as Soluplus).

In one or more embodiments of the present invention, the paracetamol sustained-release preparation, wherein:

The plasticizer is any one or more selected from poloxamer 407, PEG6000 and triethyl citrate.

In one or more embodiments of the present invention, the paracetamol sustained-release preparation, wherein:

The disintegrant does not include CMS-Na and CCNa;

Preferably, the disintegrant is crospovidone (for example, Kollidon cl-F).

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

Paracetamol 175-200 parts by weight

Kollidon VA64 175-300 parts by weight

Poloxamer 407 20-30 parts by weight, for example 25 parts by weight.

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

175 parts by weight of acetaminophen

Kollidon VA64 175-300 parts by weight

Poloxamer 407 20-30 parts by weight, for example 25 parts by weight.

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

200 parts by weight of acetaminophen

Kollidon VA64 175-300 parts by weight

Poloxamer 407 20-30 parts by weight, for example 25 parts by weight.

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

Paracetamol 175-200 parts by weight

Kollidon VA64 175 parts by weight

Poloxamer 407 20-30 parts by weight, for example 25 parts by weight.

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

Paracetamol 175-200 parts by weight

Kollidon VA64 300 parts by weight

Poloxamer 407 20-30 parts by weight, for example 25 parts by weight.

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

175 parts by weight of acetaminophen

Kollidon VA64 175 parts by weight

Poloxamer 407 20-30 parts by weight, for example 25 parts by weight.

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

175 parts by weight of acetaminophen

Kollidon VA64 300 parts by weight

Poloxamer 407 20-30 parts by weight, for example 25 parts by weight.

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

200 parts by weight of acetaminophen

Kollidon VA64 175 parts by weight

Poloxamer 407 20-30 parts by weight, for example 25 parts by weight.

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

200 parts by weight of acetaminophen

Kollidon VA64 300 parts by weight

Poloxamer 407 20-30 parts by weight, for example 25 parts by weight.

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

In one or more embodiments of the present invention, the paracetamol sustained-release preparation includes the following components:

In one or more embodiments of the present invention, the paracetamol sustained-release preparation is a paracetamol sustained-release tablet.

In one or more embodiments of the present invention, the acetaminophen sustained-release preparation, wherein the acetaminophen drug loading amount is less than or equal to 35%.

In one or more embodiments of the present invention, the acetaminophen sustained-release preparation, wherein the acetaminophen drug loading amount is less than or equal to 40%.

In one or more embodiments of the present invention, the paracetamol sustained-release preparation, the hot-melt extrusion matrix, such as copovidone, especially Kollidon VA64, has a weight percentage content of greater than or equal to 65%, greater than Or equal to 70%, 65%-80%, 65%-70%, or 70%-80%.

In one or more embodiments of the present invention, in the paracetamol sustained-release preparation, the plasticizer, such as poloxamer 407 or PEG6000, has a weight percentage content of 3%-15%, 3%- 10%, 3%-5%, 5%-15%, 5%-10%, 3%, 5%, 10% or 15%; preferably 3%-10%, more preferably 3%-5%.

In one or more embodiments of the present invention, in the paracetamol sustained-release preparation, the disintegrant, such as crospovidone, especially Kollidon cl-F, has a weight percentage content of less than or equal to 20% , Less than or equal to 15%, less than or equal to 10%, less than or equal to 5%, 5%-20%, 5%-15%, 5%-10%, 5%, 10%, 15%, 20% or 0.

In one or more embodiments of the present invention, the paracetamol sustained-release preparation is enteric-soluble or gastric-soluble.

In one or more embodiments of the present invention, the paracetamol sustained-release preparation is prepared by the following preparation method of the present invention.

In one or more embodiments of the present invention, the paracetamol sustained-release preparation is prepared by 3D printing through hot melt extrusion molding technology after mixing the components; preferably, the 3D printed The line spacing is 0.5-1.5mm, preferably 0.7-1.1mm or 0.7-0.9mm, for example 0.7mm, 0.8mm, 0.9mm, 1.0mm or 1.1mm.

In one or more embodiments of the present invention, when the acetaminophen sustained-release preparation is Kollidon VA64 as the hot-melt extrusion matrix, it preferably does not contain a disintegrant, especially does not contain Kollidon cl-F; and The line spacing of 3D printing is 0.7-0.9mm, such as 0.7mm, 0.8mm or 0.9mm.

In one or more embodiments of the present invention, the paracetamol sustained-release preparation, when the hot-melt extrusion matrix is Soluplus, preferably contains a disintegrant, especially Kollidon cl-F, Kollidon cl-F For example, the content of Kollidon cl-F is 5%-20%, 5%-15%, 5%-10%, 10%-20% or 15%-20%; and the line spacing of 3D printing is 1.0-1.1mm .

Another aspect of the present invention relates to a method for preparing the paracetamol sustained-release preparation according to any one of the present invention, including the step of 3D printing by hot melt extrusion molding technology after mixing the components;

Preferably, the printing temperature is 140°C to 175°C, preferably 145°C to 175°C, 145°C to 160°C, 145°C to 155°C, 150°C to 175°C, 150°C to 155°C or 155°C to 175°C;

Preferably, the layer height is 0.6-0.8mm, preferably 0.7mm;

Preferably, the line spacing is 0.5-1.5mm, preferably 0.7-1.1mm, 0.7-0.9mm or 1.0-1.1mm, such as 0.7mm, 0.8mm, 0.9mm, 1.0mm or 1.1mm.

In one embodiment of the present invention, the equipment for preparing acetaminophen sustained-release tablets is shown in Figure 1. It consists of a generator, a cylinder, a piston rod, a thermocouple, a nozzle and a workbench. During the operation, the entire equipment It can move freely on the X-axis, Y-axis, and Z-axis, add the material to the cylinder, heat up the material in the cylinder through the thermocouple, and extrude the material from the nozzle after the material is melted by the extrusion of the piston rod Go to the workbench, and print layer by layer by moving the device in the X, Y, and Z directions.

In one or more embodiments of the present invention, the preparation method includes the following steps:

Use computer software to draw the model of the tablet;

Input the solid dosage model into the software of the printer;

Mix the medicine and excipients evenly;

Determine the dropping point, softening point and rheological properties of the material, and determine the printing temperature range of the material;

Add the mixed material to the cylinder, raise the temperature, lower the piston rod of the equipment to compress, keep it warm for a period of time, until the nozzle has the material to be extruded;

Adjust the Z axis to make the distance to the printing plate appropriate, and adjust the nozzle speed and piston rod extrusion speed for printing;

After the printing is finished, the preparation is removed from the printing plate after the preparation is solidified.

In one or more embodiments of the present invention, the nozzle can be a dispensing needle, the length of the needle is 0.5-2mm, and the inner diameter of the nozzle is 0.3-0.8mm;

In one or more embodiments of the present invention, the initial distance between the Z axis and the printing plate can be adjusted according to different nozzle diameters, and the general range is 0.4-1.0mm;

In one or more embodiments of the present invention, the moving speed of the nozzle may be 4-10mm/s;

In one or more embodiments of the present invention, the extrusion speed of the piston rod may be 0.01-0.1 mm/s;

In one or more embodiments of the present invention, the printing plate may be an acrylic glass plate, a metal plate, etc.;

In one or more embodiments of the present invention, the release rate of the drug is adjusted by adjusting the size of the print line spacing;

In one or more embodiments of the present invention, the in vitro release time of the sustained-release tablet should be controlled between 6h-24h.

In one or more embodiments of the present invention, the preparation method includes the following steps:

(1) Mix the materials according to the prescription composition for 30 minutes;

(2) Add the mixed material to the cylinder of the printer, lower the T axis of the printer and compact the material;

(3) Raise the temperature to 145℃-155℃ and keep it for 30min;

(4) The selected nozzle is a dispensing nozzle with an inner diameter of 0.5mm and a length of 2mm. Adjust the height of the Z axis so that the distance between the nozzle and the printing plate is 0.4mm, adjust the movement speed of the printer nozzle to 8mm/s, and adjust the extrusion speed of the printer piston rod as 0.015mm/s, layer height 0.7mm, line spacing 0.7mm.

(5) Call the print model, the designed model is in the shape of a tablet, the height of the tablet is 6mm, and the diameter is 13mm;

(6) Start the printer to start printing, cool down for 1 min after printing, remove the tablet from the first printing plate, and continue printing the next slice.

The invention also relates to an acetaminophen sustained-release preparation, which is prepared by the preparation method of the invention.

The acetaminophen sustained-release preparation according to any one of the present invention is used for antipyretic and/or analgesia;

Preferably, the antipyretic is to treat and/or relieve fever caused by a cold;

Preferably, the analgesia is the treatment and/or alleviation of headache caused by a cold, or the treatment and/or alleviation of arthralgia, muscle pain, neuralgia, migraine, dysmenorrhea, cancer pain, or pain after surgery.

Another aspect of the present invention relates to the use of the acetaminophen sustained-release preparation of any one of the present invention in the preparation of a medicine for antipyretic and/or analgesia;

Preferably, the antipyretic is to treat and/or relieve fever caused by a cold;

Preferably, the analgesia is the treatment and/or alleviation of headache caused by a cold, or the treatment and/or alleviation of arthralgia, muscle pain, neuralgia, migraine, dysmenorrhea, cancer pain, or pain after surgery.

Another aspect of the present invention relates to a method for antipyretic and/or analgesia, comprising the step of administering an effective amount of the paracetamol sustained-release preparation according to any one of the present invention to a subject in need;

Preferably, the antipyretic is to treat and/or relieve fever caused by a cold;

Preferably, the analgesia is the treatment and/or alleviation of headache caused by a cold, or the treatment and/or alleviation of arthralgia, muscle pain, neuralgia, migraine, dysmenorrhea, cancer pain, or pain after surgery.

The only active ingredient in the paracetamol sustained-release preparation of the present invention is paracetamol. Considering that acetaminophen is a relatively mature drug, the dosage of acetaminophen can be administered according to conventional practices in the field (such as pharmacopoeia or pharmacy manuals, etc.), and then converted into the dosage of acetaminophen sustained-release preparations. In addition, those skilled in the art can also understand that the dosage depends on many factors, such as the severity of the disease and/or condition being treated, the gender, age, weight and individual response of the patient or animal, as well as the condition and condition of the patient to be treated. Past medical history is selected. The common practice in the art is to start the dosage from a level lower than the level required to obtain the desired therapeutic effect, and gradually increase the dosage until the desired effect is obtained.

In the present invention,

The term "printing temperature" refers to the temperature set in the printing chamber during printing. Printing temperature largely determines the success or failure of printing.

The term "layer height" refers to the distance raised in the Z axis during printing. The layer height affects the appearance of the tablet. If the parameter is set too high, the tablet will collapse, and if it is set too low, the middle part of the tablet will be higher than the surrounding area.

The term "line spacing" refers to the distance between the filaments in each layer during the printing process. The line spacing affects the appearance and release of the tablet.

The term "effective amount" refers to a dose that can treat, prevent, alleviate and/or alleviate the disease or condition described in the present invention in a subject.

The term "subject" may refer to patients or other animals receiving the pharmaceutical composition of the present invention to treat, prevent, alleviate and/or alleviate the diseases or conditions of the present invention, especially mammals, such as humans, dogs, monkeys, cows , Horse, etc.

The term "disease and/or disorder" refers to a physical state of the subject, which physical state is related to the disease and/or disorder described in the present invention.

The beneficial effects of the invention

The present invention has achieved one or more of the following technical effects:

(1) The present invention has successfully developed a sustained-release acetaminophen pharmaceutical composition suitable for 3D printing, particularly suitable for the combined use of HME and FDM, a sustained-release acetaminophen preparation (such as a sustained-release tablet) and a preparation method thereof.

(2) The acetaminophen sustained-release preparation of the present invention has good sustained-release performance.

(3) Compared with the same drugs on the market, the paracetamol sustained-release tablets prepared by the present invention have the advantages of adjustable specification, size and shape, and can be individualized for different groups of people, such as those with poor liver function. The elderly and children can be given a low-dose tablet, and for people with normal liver function, a normal dose can be given.

(4) The paracetamol sustained-release tablets prepared by the present invention can be controlled and adjusted through different materials and internal structures.

Description of the drawings

Figure 1: Schematic diagram of hot melt extrusion and 3D printing equipment. 1: Motor; 2: Piston; 3: Cylinder; 4: Thermocouple; 5: Feeding chamber; 6: Nozzle; 7: Printing board.

Detailed ways

The embodiments of the present invention will be described in detail below in conjunction with examples, but those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. If no specific conditions are indicated in the examples, the routine conditions or the conditions recommended by the manufacturer shall be followed. The reagents or instruments used without the manufacturer's indication are all conventional products that can be purchased on the market.

In the present invention,

Kollidon VA64 is a kind of copovidone, a product of BASF company, import registration certificate: F20160008, DMF number: 6745;

Kollidon cl-F is a kind of cross-linked povidone, a product of BASF company, particle size: 20-40μm; DMF number: 22604);

Soluplus is a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, a product of BASF company, DMF number: 23504.

Preparation Example 1: Preparation of Paracetamol Sustained-Release Tablets (1)

Prescription composition

Tablet printing

(1) Mix the materials according to the prescription composition for 30 minutes;

(2) Add the mixed material to the cylinder of the printer, lower the T axis of the printer and compact the material;

(3) Raise the temperature to 145℃-155℃ and keep it for 30min;

(4) The selected nozzle is a dispensing nozzle with an inner diameter of 0.5mm and a length of 2mm. Adjust the height of the Z axis so that the distance between the nozzle and the printing plate is 0.4mm, adjust the movement speed of the printer nozzle to 8mm/s, and adjust the extrusion speed of the printer piston rod as 0.015mm/s, layer height 0.7mm, line spacing 0.7mm.

(5) Call the print model, the designed model is in the shape of a tablet, the height of the tablet is 6mm, and the diameter is 13mm;

(6) Start the printer to start printing, cool down for 1 min after printing, remove the tablet from the first printing plate, and continue printing the next slice.

result:

Obtained a transparent round tablet, the tablet hardness is large, the appearance is good, indicating gloss.

Preparation Example 2: Preparation of Paracetamol Sustained-Release Tablets

Prescription composition

Tablet printing

The printing temperature is 160°C, and the remaining steps are the same as in Preparation Example 1.

Result: The printed light yellow transparent round tablets have a glossy surface, good appearance and high hardness.

Test Example 1: Prescription and Process Research (1)

The preparation process refers to the preparation example 1 above.

1. Drug loading study

As shown in Table 1 below.

Table 1

prescription	Acetaminophen	Kollidon VA64
1-1	20%	80%
1-2	30%	70%
1-3	35%	65%
1-4	40%	60%
1-5	50%	50%

result:

The results show that prescriptions 1-1, 1-2, and 1-3 can be successfully printed into tablets, while prescriptions 1-4 and 1-5 cannot be printed successfully due to uneven extrusion of the melt, because the printing process is due to the loading of drugs. If the amount is too large, the content of acetaminophen that can be carried by the hot-melt matrix Kollidon VA64 is limited. Therefore, the results show that the maximum acetaminophen drug load that Kollidon VA64 can carry is about 35%.

2. The influence of plasticizers on printing

As shown in Table 2 below.

Table 2

prescription	Acetaminophen	Kollidon VA64	Poloxamer 407	PEG6000
2-1	35%	60%	5%	/
2-2	35%	55%	10%	/
2-3	35%	50%	15%	/
2-4	35%	60%	/	5%

2-5	35%	55%	/	10%
2-6	35%	50%	/	15%
2-7	35%	62%	3%	/
2-8	35%	62%	/	3%

The results are shown in Table 3 below.

table 3

prescription	Printing temperature (℃)	Exterior
2-1	150	Milky white round tablets
2-2	145	Milky white round tablet, slightly collapsed
2-3	135	Milky white round tablet with obvious collapse
2-4	155	Milky white round tablets
2-5	147	Milky white round tablet with obvious collapse
2-6	142	Milky white round tablet with obvious collapse
2-7	152	Milky white round tablets
2-8	156	Milky white round tablets

the result shows:

After the plasticizer poloxamer 407 is added, the printing temperature decreases, and with the increase of the added amount, the more the temperature decreases, and the softer the molten material formed, but too much addition will cause the material to be too soft and make the material too soft. Collapse the tablet;

The tablet with 5% plasticizer PEG6000 has a good appearance. Adding more than 5% will cause the tablet to collapse. However, the tablet with PEG6000 will have a higher printing temperature than Poloxamer 407. Therefore, the low temperature should be ensured at the same time. In the case of appearance, it is preferable to add poloxamer 407 to 5%.

Lowering the printing temperature can further ensure the stability of the material, and can increase the toughness of the extruded material, reduce the brittleness, and make printing easier. If Boloxamer 407 is not added, it cannot be extruded at low temperature.

3. The influence of disintegrant on printing

As shown in Table 4 below.

Table 4

The results are shown in Table 5 below.

table 5

prescription	Printing temperature (℃)	Exterior
3-1	155	Milky white round tablets
3-2	160	Milky white round tablets
3-3	170	Milky white round tablets
3-4	185	Yellow round tablet
3-5	/	Print failed
3-6	/	Print failed

The results show that the tablet can still be printed after adding the disintegrant Kollidon cl-F, but it will increase the printing temperature, and the larger the added amount, the more obvious the temperature will increase. When the added amount reaches 25%, the printing temperature will increase. At 185°C, the printed tablet turns yellow. The color of the material itself is light yellow, but the darkening of the yellow color indicates to a certain extent that the material has undergone a certain change, and it is best to discard it. Therefore, the maximum addition amount of the disintegrant Kollidon cl-F is 20%.

After adding disintegrants CMS-Na and CCNa, after adjusting the printing temperature and various parameters, it still cannot print. The material is extruded intermittently and cannot be formed, indicating that these two disintegrants cannot be added as hot melt printing here. Material use.

Test Example 2: In vitro release test (1)

For the preparation process of each prescription, refer to Preparation Example 1 above.

The dissolution method is shown in Table 6 below.

Table 6

Dissolution method	Paddle method
Dissolution medium	pH1.2 hydrochloric acid
Medium volume	900ml
Dissolution temperature	37°C
Rotating speed	50rpm
Cups	6 cups

4. The effect of disintegrant on in vitro release

As shown in Table 7 below.

Table 7

prescription	Acetaminophen	Kollidon VA64	Poloxamer 407	Kollidon cl-F
4-1	35%	60%	5%	/
4-2	35%	50%	5%	10%
4-3	35%	45%	5%	15%
4-4	35%	40%	5%	20%

The results are shown in Table 8 below.

Table 8

To	0.5h dissolution	1h dissolution rate	3h dissolution
4-1	37.95%	66.91%	99.87%
4-2	27.08%	47.17%	90.43%
4-3	28.00%	47.81%	91.36%
4-4	28.23%	48.37%	90.08%

Results: The results showed that the addition of the disintegrant Kollidon cl-F under the experimental conditions did not accelerate the dissolution of the tablet, and on the contrary, it slowed down the dissolution rate, indicating that the disintegrant Kollidon cl-F could not be under the conditions of hot-melt extrusion. Play the effect of promoting the dissolution of drugs. Those skilled in the art know that in general, the disintegrant increases the dissolution rate, but it does not play a corresponding role here.

5. The effect of line spacing on in vitro release

As shown in Table 9 below.

Table 9

The results are shown in Table 10 below.

Table 10

To	0.5h dissolution	1h dissolution rate	2h dissolution rate	3h dissolution
5-1	37.95%	66.91%	89.04%	99.87%
5-2	40.31%	68.26%	92.85%	99.35%
5-3	75.97%	90.46%	98.21%	99.62%

Results: The results showed that the release rate of tablets with different line spacings in vitro was significantly different, and the larger the line spacing, the faster the dissolution. Three kinds of tablets with different line spacings could achieve different releases. When the line spacing is 0.7 or 0.9mm, it can be released. As a sustained-release tablet, the release is completed within 3 hours in the stomach; when the line spacing is 1.1 mm, it can be used as a normal tablet, and the release rate in the stomach is greater than 80% within 1 hour.

Test Example 3: Prescription and Process Research (2)

For the preparation process of each prescription, refer to Preparation Example 1 above.

6. Drug loading research

As shown in Table 11 below.

Table 11

prescription	Acetaminophen	soluplus
6-1	20%	80%
6-2	30%	70%

6-3	40%	60%
6-4	45%	55%
6-5	50%	50%

result:

The results show that prescriptions 6-1, 6-2, and 6-3 can be successfully printed into tablets, while prescriptions 6-4 and 6-5 cannot be printed successfully due to uneven extrusion of the melt because of the drug loading during the printing process. If the amount is too large, the content of paracetamol that can be carried by the hot-melt matrix soluplus is limited. Therefore, the results show that the maximum drug loading of paracetamol that can be carried by soluplus is about 40%.

7. The effect of plasticizer on printing

As shown in Table 12 below.

Table 12

prescription	Acetaminophen	soluplus	Poloxamer 407
7-1	40%	55%	5%
7-2	40%	50%	10%
7-3	40%	45%	15%
7-4	40%	57%	3%

The results are shown in Table 13 below.

Table 13

prescription	Printing temperature (℃)	Exterior
7-1	155	Light yellow round tablet
7-2	150	Light yellow round tablet, slightly collapsed
7-3	140	Light yellow round tablet with obvious collapse
7-4	158	Light yellow round tablet

As in Preparation Example 1, the printing temperature can be lowered after adding Poloxamer 407, and the more the amount added, the lower the temperature, the softer the extruded molten material, and the appearance of the tablet changes from light yellow transparent to light yellow opaque. However, too much addition will make the tablet too soft and difficult to collapse. Therefore, the addition of poloxamer 407 in the printed tablet with soluplus as the hot-melt matrix is 5%.

8. The influence of disintegrant on printing

As shown in Table 14 below.

Table 14

The results are shown in Table 15 below.

Table 15

prescription	Printing temperature (℃)	Exterior
8-1	160	Light yellow round tablet
8-2	165	Light yellow round tablet
8-3	175	Light yellow round tablet
8-4	200	Yellow round tablet
8-5	/	Print failed
8-6	/	Print failed

After adding 10% Kollidoncl-F, it can be printed successfully, and the temperature is lower, and the tablet color and appearance are better. Adding 20% or more of Kollidoncl-F makes the printing temperature rise significantly and the tablet color becomes darker. Conducive to the thermal stability of the material and the darkening of the color will be questioned whether degradation has occurred, and will generally be discarded. In addition, the addition of CMS-Na and CCNa cannot print successfully, which is manifested in that the melt is not uniformly extruded (uneven thickness and speed) and cannot be formed.

Test Example 4: In vitro release test (2)

For the preparation process of each prescription, refer to Preparation Example 1 above.

Dissolution method

As shown in Table 16 below.

Table 16

Dissolution method	Paddle method
Dissolution medium	pH6.8 phosphate buffer
Medium volume	900ml
Dissolution temperature	37°C
Rotating speed	50rpm
Cups	6 cups

9. The influence of disintegrant content on in vitro release

Prescription composition

As shown in Table 17 below.

Table 17

prescription	Acetaminophen	soluplus	Poloxamer 407	Kollidon cl-F
9-1	40%	45%	5%	10%
9-2	40%	40%	5%	15%
9-3	40%	35%	5%	20%

The results are shown in Table 18 below.

Table 18

To	0.5h dissolution	3h dissolution	12h dissolution rate	Dissolution rate in 24h
9-1	6.09%	15.36%	28.75%	43.40%
9-2	8.26%	19.67%	36.23%	49.98%
9-3	9.44%	27.41%	48.03%	58.55%

The results show that the addition of Kollidon cl-F to the acetaminophen printed tablets based on soluplus can accelerate the dissolution rate of the tablet. The tablet in vitro release increases with the addition of Kollidon cl-F, and the dissolution behavior The change occurs. The tablets with less than 20% Kollidon cl-F dissolve in a dissolving manner, while the tablets with 20% disintegrant disintegrate, and they are released by disintegration and dissolution at the same time. There is no difference between the two methods themselves, it mainly depends on whether the dissolution rate can meet the requirements.

In addition, gastric dissolution should usually be faster due to gastric emptying (the United States Pharmacopoeia requires 80% in 3 hours), and enteric-coated drugs can be prolonged due to the longer residence time of the drug in the intestinal tract, through different materials and ratios. The form of dissolution and the time of dissolution can be adjusted.

10. The effect of line spacing on in vitro release

As shown in Table 19 below.

Table 19

The results are shown in Table 20 below.

Table 20

To	0.5h dissolution	3h dissolution	12h dissolution rate	Dissolution rate in 24h
10-1	9.44%	27.41%	48.03%	58.55%
10-2	10.55%	29.83%	53.54%	66.95%
10-3	23.92%	58.97%	87.03%	91.93%

The results show that for the same prescription, tablets with soluplus as the matrix have different velvet acceleration speeds with different line spacing. The larger the line spacing, the faster the dissolution. When the line spacing is 1.1mm, the 12h dissolution rate is >80%, which can be completed. Good dissolution in the intestine.

Although the specific embodiments of the present invention have been described in detail, those skilled in the art will understand. According to all the teachings that have been disclosed, various modifications and substitutions can be made to those details, and these changes are within the protection scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims (13)

1. An acetaminophen sustained-release preparation, including the following components:

   
2. The acetaminophen sustained-release preparation according to claim 1, wherein:

   The hot melt extrusion matrix is selected from one or more of copovidone (such as Kollidon VA64) and polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (such as Soluplus).
3. The acetaminophen sustained-release preparation according to any one of claims 1 to 2, wherein:

   The plasticizer is any one or more selected from poloxamer 407, PEG6000 and triethyl citrate.
4. The acetaminophen sustained-release preparation according to any one of claims 1 to 3, wherein:

   The disintegrant does not include CMS-Na and CCNa;

   Preferably, the disintegrant is crospovidone (for example, Kollidon cl-F).
5. The acetaminophen sustained-release preparation according to any one of claims 1 to 4, comprising the following components:

   
6. The acetaminophen sustained-release preparation according to any one of claims 1 to 5, comprising the following components:

   Paracetamol 175-200 parts by weight

   Kollidon VA64 175-300 parts by weight

   Poloxamer 407 20-30 parts by weight, for example 25 parts by weight;

   Preferably, the following components are included:

   Paracetamol 175 parts by weight

   Kollidon VA64 300 parts by weight

   Poloxamer 407 20-30 parts by weight, such as 25 parts by weight.
7. The acetaminophen sustained-release preparation according to any one of claims 1 to 5, comprising the following components:

   

   Preferably, the following components are included:

   
8. The acetaminophen sustained-release preparation according to any one of claims 1 to 7, which is an acetaminophen sustained-release tablet.
9. The paracetamol sustained-release preparation according to any one of claims 1 to 8, which is prepared by a preparation method comprising the steps of: mixing the components and then performing 3D printing by hot-melt extrusion molding technology;

   Preferably, the printing temperature is 140°C to 175°C, preferably 145°C to 175°C, 145°C to 155°C, 150°C to 175°C, 150°C to 155°C or 155°C to 175°C;

   Preferably, the layer height is 0.6-0.8mm, preferably 0.7mm;

   Preferably, the line spacing is 0.5-1.5 mm, preferably 0.7-1.1 mm, more preferably 0.7-0.9 mm or 1.0-1.1 mm.
10. A method for preparing the paracetamol sustained-release preparation according to any one of claims 1 to 8, comprising the step of 3D printing by hot melt extrusion molding technology after mixing the components;

    Preferably, the printing temperature is 140°C to 175°C, preferably 145°C to 175°C, 145°C to 155°C, 150°C to 175°C, 150°C to 155°C or 155°C to 175°C;

    Preferably, the layer height is 0.6-0.8mm, preferably 0.7mm;

    Preferably, the line spacing is 0.5-1.5 mm, preferably 0.7-1.1 mm, more preferably 0.7-0.9 mm or 1.0-1.1 mm.
11. Use of the acetaminophen sustained-release preparation according to any one of claims 1 to 9 in the preparation of a medicament for antipyretic and/or analgesia;

    Preferably, the antipyretic is to treat and/or relieve fever caused by a cold;

    Preferably, the analgesia is the treatment and/or alleviation of headache caused by a cold, or the treatment and/or alleviation of arthralgia, muscle pain, neuralgia, migraine, dysmenorrhea, cancer pain, or pain after surgery.
12. The acetaminophen sustained-release preparation according to any one of claims 1 to 9, which is used for antipyretic and/or analgesia;

    Preferably, the antipyretic is to treat and/or relieve fever caused by a cold;

    Preferably, the analgesia is the treatment and/or alleviation of headache caused by a cold, or the treatment and/or alleviation of arthralgia, muscle pain, neuralgia, migraine, dysmenorrhea, cancer pain, or pain after surgery.
13. An antipyretic and/or analgesic method, comprising the step of administering an effective amount of the paracetamol sustained-release preparation according to any one of claims 1 to 9 to a subject in need;

    Preferably, the antipyretic is to treat and/or relieve fever caused by a cold;

    Preferably, the analgesia is the treatment and/or alleviation of headache caused by a cold, or the treatment and/or alleviation of arthralgia, muscle pain, neuralgia, migraine, dysmenorrhea, cancer pain, or pain after surgery.

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