CN110585156B

CN110585156B - Acetaminophen sustained-release preparation and 3D printing preparation method thereof

Info

Publication number: CN110585156B
Application number: CN201911014428.0A
Authority: CN
Inventors: 郑爱萍; 王增明; 刘伯石; 韩晓璐; 张慧; 高静; 李蒙; 高翔; 刘楠
Original assignee: Academy of Military Medical Sciences AMMS of PLA
Current assignee: Academy of Military Medical Sciences AMMS of PLA
Priority date: 2019-10-24
Filing date: 2019-10-24
Publication date: 2021-09-28
Anticipated expiration: 2039-10-24
Also published as: WO2021077889A1; CN110585156A

Abstract

The invention belongs to the field of medicines and preparations, and discloses a paracetamol sustained release preparation and a 3D printing preparation method thereof. Specifically, the invention relates to a paracetamol sustained release tablet and a method for preparing the paracetamol sustained release tablet by using a 3D printing technology. More specifically, the invention relates to a paracetamol sustained release preparation, which comprises the following components: 250 parts by weight of acetaminophen; 150-350 parts by weight of hot-melt extrusion matrix; 15-35 parts by weight of a plasticizer; 0-150 parts of disintegrating agent. The acetaminophen slow release preparation has high drug loading and good slow release effect.

Description

Acetaminophen sustained-release preparation and 3D printing preparation method thereof

Technical Field

The invention belongs to the field of medicines and preparations, and discloses a paracetamol sustained release preparation and a 3D printing preparation method thereof. Specifically, the invention relates to a paracetamol sustained release tablet and a method for preparing the paracetamol sustained release tablet by using a 3D printing technology.

Background

Acetaminophen (Paracetamol) is a common antipyretic analgesic that selectively inhibits synthesis of central prostaglandins by inhibiting cyclooxygenase, resulting in peripheral vasodilation and sweating, and has a similar intensity of antipyretic action to aspirin; the traditional Chinese medicine composition has an analgesic effect by inhibiting synthesis and release of prostaglandin and the like and increasing pain threshold, belongs to a peripheral analgesic, has weaker effect than aspirin, and is only effective on light and moderate pain. The product has no obvious anti-inflammatory effect. Acetaminophen is mainly used for fever and headache caused by cold, relieving mild and moderate pain, such as arthralgia, myalgia, neuralgia, migraine, dysmenorrhea, cancer pain, postoperative analgesia, etc. It is also useful in patients who are allergic to aspirin, intolerant of aspirin, or who are not eligible for aspirin: such as varicella, hemophilia and other hemorrhagic disease patients (including patients applying anticoagulation therapy), and patients with light peptic ulcer and gastritis. The structural formula of the acetaminophen is shown as the following formula A.

Tylonel is the only paracetamol sustained release tablet single formulation currently on the market in the United states, is listed as a reference formulation and a standard formulation by American orange peel book, and has the specification of 650 mg. The acetaminophen sustained-release tablets on the market at present are tylonolin and Beilecin, and the specifications of the acetaminophen sustained-release tablets are 650 mg.

However, in 2011 the united states Food and Drug Administration (FDA) issued recommendations for reducing the prescription specification of acetaminophen, i.e., no more than 325mg per tablet, to reduce liver damage. Therefore, the acetaminophen sustained-release tablets on the market at present have large specifications and have potential liver damage risks, so the acetaminophen sustained-release tablets with small specifications are needed to achieve the same treatment purpose.

Hot Melt Extrusion (HME), which is a process of forming a material into a uniformly shaped object through a specific die under a condition of elevated temperature, was first used in the plastic industry, and since the 80 s of the 20 th century, it was applied to the pharmaceutical industry to solubilize poorly soluble drugs and mask bitter drugs, which is a good pharmaceutical means. Hot melt extrusion can be divided into ram extrusion, in which a material melted by heating is extruded through a die orifice, and screw extrusion, in which a material melted by rotation of a screw is extruded.

Fused Deposition Modeling (FDM) printing is one of 3D printing technologies, which is to prepare a material into a wire with a certain diameter and good printability, and then print the wire layer by layer. The technical method is simple, equipment is simplified, the method is a good 3D printing technology, research on the technology in the pharmaceutical field is gradually increased in recent years, but the preparation of the wire in the preparation process is difficult, the prepared wire has good printing performance and can be printed and formed by a printer, if the wire does not meet a series of requirements on hardness, toughness and the like, printing cannot be successfully carried out, so that high requirements on materials and preparation processes are provided, and difficulty is added for 3D printing.

The hot-melt extrusion type FDM combines HME and FDM, a drug, a polymer and other auxiliary materials (such as a plasticizer) are fully mixed and then are heated and extruded by a hot extruder to prepare a drug-containing polymer wire material for 3D printing, the drug release characteristics can be regulated and controlled by changing the shape, changing the printing polymer material, changing the printing dosage form and the like, and the efficiency is improved in the aspect of preparing a solid drug dosage form.

However, the requirements of the drug in HME-FDM combination, such as the necessary thermal stability, the necessary thermoplastic properties of the polymer, and biodegradability, limit the range of applications of the drug and the polymer material. There are also drug loading limitations for the pharmaceutical dosage forms prepared: the drug loading is too low to reach the required dosage; too high may affect drug-polymer binding. In addition, the composition of the current 3D printing pharmaceutical preparation is relatively simple, the pharmaceutical preparation is mostly a binary system of a drug and a polymer, and whether more other auxiliary materials can be introduced or not 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 difficulties in the art.

Currently, there is a need to develop a novel acetaminophen sustained release formulation and a method for preparing the same by studying an acetaminophen sustained release pharmaceutical composition (prescription) suitable for 3D printing, particularly suitable for HME and FDM in combination.

Disclosure of Invention

The inventor of the invention obtains an acetaminophen sustained-release pharmaceutical composition (prescription) suitable for 3D printing, particularly suitable for combining HME and FDM through intensive research and creative work, and develops a novel acetaminophen sustained-release preparation (such as sustained-release tablet) and a preparation method thereof on the basis of the acetaminophen sustained-release pharmaceutical composition (prescription). The acetaminophen slow-release preparation is very suitable for being prepared by 3D printing, particularly 3D printing combining HME and FDM, and has a good slow-release effect. The following invention is thus provided:

one aspect of the invention relates to a paracetamol sustained release preparation, which comprises the following components:

in one or more embodiments of the present invention, the acetaminophen sustained-release preparation, wherein,

the hot melt extruded matrix is selected from:

one or more of copovidone (e.g., Kollidon VA64) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (e.g., Soluplus).

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

the disintegrant does not comprise CMS-Na and CCNa;

preferably, the disintegrant is crospovidone (e.g., Kollidon cl-F).

In one or more embodiments of the present invention, the acetaminophen sustained release formulation comprises the following components:

acetaminophen 175-200 weight portions

Kollidon VA 64175-300 weight parts

Poloxamer 40720-30 parts by weight, for example 25 parts by weight.

acetaminophen 175 weight part

Kollidon VA 64175-300 weight parts

Poloxamer 40720-30 parts by weight, for example 25 parts by weight.

200 parts by weight of acetaminophen

Kollidon VA 64175-300 weight parts

Poloxamer 40720-30 parts by weight, for example 25 parts by weight.

acetaminophen 175-200 weight portions

Kollidon VA 64175 parts by weight

Poloxamer 40720-30 parts by weight, for example 25 parts by weight.

acetaminophen 175-200 weight portions

Kollidon VA 64300 parts by weight

Poloxamer 40720-30 parts by weight, for example 25 parts by weight.

acetaminophen 175 weight part

Kollidon VA 64175 parts by weight

Poloxamer 40720-30 parts by weight, for example 25 parts by weight.

acetaminophen 175 weight part

Kollidon VA 64300 parts by weight

Poloxamer 40720-30 parts by weight, for example 25 parts by weight.

200 parts by weight of acetaminophen

Kollidon VA 64175 parts by weight

Poloxamer 40720-30 parts by weight, for example 25 parts by weight.

200 parts by weight of acetaminophen

Kollidon VA 64300 parts by weight

Poloxamer 40720-30 parts by weight, for example 25 parts by weight.

in one or more embodiments of the present invention, the acetaminophen sustained-release preparation is an acetaminophen sustained-release tablet.

In one or more embodiments of the present invention, the acetaminophen sustained release formulation wherein the acetaminophen drug load is 35% or less.

In one or more embodiments of the present invention, the acetaminophen sustained release formulation wherein the acetaminophen drug load is less than or equal to 40%.

In one or more embodiments of the invention, the acetaminophen sustained release formulation, the hot melt extruded matrix, such as copovidone, and in particular Kollidon VA64, is present in an amount of greater than or equal to 65%, greater than or equal to 70%, 65% to 80%, 65% to 70%, or 70% to 80% by weight.

In one or more embodiments of the present invention, the acetaminophen sustained release preparation contains 3% to 15%, 3% to 10%, 3% to 5%, 5% to 15%, 5% to 10%, 3%, 5%, 10%, or 15% by weight of the plasticizer, such as poloxamer 407 or PEG 6000; preferably 3% to 10%, more preferably 3% to 5%.

In one or more embodiments of the invention, the acetaminophen sustained release formulation, the disintegrant, e.g., crospovidone, and in particular Kollidon cl-F, is present in an amount 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% by weight.

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

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

In one or more embodiments of the invention, the acetaminophen sustained-release preparation is prepared by mixing the components and performing 3D printing by a hot-melt extrusion molding technology; preferably, the line spacing for 3D printing is 0.5-1.5mm, preferably 0.7-1.1mm or 0.7-0.9mm, e.g. 0.7mm, 0.8mm, 0.9mm, 1.0mm or 1.1 mm.

In one or more embodiments of the invention, the acetaminophen sustained release formulation, when the hot-melt extruded matrix is Kollidon VA64, is preferably free of disintegrant, particularly Kollidon cl-F; and the line spacing for 3D printing is 0.7-0.9mm, for example 0.7mm, 0.8mm or 0.9 mm.

In one or more embodiments of the invention, the acetaminophen sustained release formulation, when the hot melt extruded matrix is Soluplus, preferably contains a disintegrant, particularly Kollidon cl-F, e.g., Kollidon cl-F in an amount of 5% to 20%, 5% to 15%, 5% to 10%, 10% to 20%, or 15% to 20%; and the line spacing for 3D printing is 1.0-1.1 mm.

Another aspect of the present invention relates to a method for preparing the acetaminophen controlled-release preparation of any one of the above embodiments, comprising the steps of mixing the components and performing 3D printing by a hot-melt extrusion molding technique;

preferably, the printing temperature is 140-175 ℃, preferably 145-175 ℃, 145-160 ℃, 145-155 ℃, 150-175 ℃, 150-155 ℃ or 155-175 ℃;

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

preferably, the line spacing is 0.5-1.5mm, preferably 0.7-1.1mm, 0.7-0.9mm or 1.0-1.1mm, for example 0.7mm, 0.8mm, 0.9mm, 1.0mm or 1.1 mm.

In one embodiment of the invention, the equipment for preparing the acetaminophen sustained-release tablet is composed of a generator, a cylinder body, a piston rod, a thermocouple, a spray head and a workbench as shown in fig. 1, during operation, the whole equipment can freely move in an X axis, a Y axis and a Z axis, materials are added into the cylinder body, the materials in the cylinder body are heated by the thermocouple, the materials are extruded from the spray head onto the workbench by the extrusion of the piston rod after being melted, and layer-by-layer stacking printing is carried out by the movement of the equipment in X, Y, Z directions.

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

using computer software to draw a model of the tablet;

inputting the solid preparation model into software of a printer;

mixing the medicine and the auxiliary materials uniformly;

measuring the drop point softening point and the rheological property of the material, and determining the printing temperature range of the material;

adding the mixed materials into a cylinder body, raising the temperature, lowering a piston rod of the equipment for compression, and preserving the heat for a period of time until the materials are extruded out of a spray head;

adjusting the distance between the Z axis and the printing plate to be proper, and adjusting the speed of the spray head and the extrusion speed of the piston rod to print;

and after the printing is finished and the preparation is solidified, removing the preparation from the printing plate.

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

in one or more embodiments of the invention, the initial distance between the Z-axis and the printing plate can be adjusted according to the diameter of the nozzle, and is generally in the range of 0.4-1.0 mm;

in one or more embodiments of the invention, the moving speed of the spray head may be in the range of 4 to 10 mm/s;

in one or more embodiments of the invention, the piston rod extrusion speed may be in the range of 0.01 to 0.1 mm/s;

in one or more embodiments of the present invention, the printing plate may be an acryl glass plate, a metal plate, or the like;

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

in one or more embodiments of the invention, the time of release of the sustained release tablet from the outside is controlled to be between 6h and 24 h.

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

(1) mixing the materials according to the prescription for 30 min;

(2) adding the mixed material into a cylinder body of a printer, descending a T shaft of the printer and compacting the material;

(3) raising the temperature to 145-155 ℃, and keeping the temperature for 30 min;

(4) the selected spray head is a glue dispensing spray head with the inner diameter of 0.5mm and the length of 2mm, the Z-axis height is adjusted to enable the distance between the spray head and the printing plate to be 0.4mm, the moving speed of the printer spray head is adjusted to be 8mm/s, the extrusion speed of a piston rod of the printer is adjusted to be 0.015mm/s, the layer height is 0.7mm, and the line spacing is 0.7 mm.

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

(6) and starting the printer to start printing, cooling for 1min after printing is finished, taking down the tablet from the first printing plate, and continuing to print the next tablet.

The invention also relates to a paracetamol sustained release preparation, which is prepared by the preparation method.

In the present invention,

the term "print temperature" refers to the temperature at which the print chamber is set when printing. The printing temperature determines the success or failure of printing.

The term "layer height" refers to the distance in the Z-axis direction that is raised during printing. The layer height affects the shape of the tablet, and if the parameter is set to be too high, the tablet collapses, and if the parameter is set to be too low, the middle part of the tablet is higher than the periphery.

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

Advantageous effects of the invention

The invention achieves one or more of the following technical effects:

(1) the invention successfully develops an acetaminophen sustained-release pharmaceutical composition, an acetaminophen sustained-release preparation (such as sustained-release tablets) and a preparation method thereof, which are suitable for 3D printing, particularly suitable for HME and FDM combined use.

(2) The acetaminophen slow release preparation has good slow release performance.

(3) Compared with the same medicine on the market, the paracetamol sustained release tablet prepared by the invention has the advantages of adjustable specification, size and shape, can be used for individual administration for different people, such as the elderly and children with poor liver function, can be used for low-dose tablets, and can be used for normal dose for people with normal liver function.

(4) The paracetamol sustained release tablet prepared by the invention can control and regulate the release through different materials and internal structures.

Drawings

FIG. 1: schematic diagram of a hot melt extrusion and 3D printing apparatus. 1: a motor; 2: a piston; 3: a cylinder; 4: a thermocouple; 5: a feeding cavity; 6: a spray head; 7: and (7) printing the plate.

Detailed Description

Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.

In the present invention,

kollidon VA64 is a copovidone, a product of BASF, imported registration: f20160008, DMF numbering: 6745;

kollidon cl-F is a crospovidone, product of BASF, particle size: 20-40 μm; DMF numbering: 22604) (ii) a

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

preparation example 1: preparation of Paracetamol extended Release tablet (1)

Prescription composition

(1) Mixing the materials according to the prescription for 30 min;

As a result:

the obtained transparent round tablet has high hardness, good appearance and luster.

Preparation example 2: preparation of acetaminophen sustained-release tablet

Prescription composition

The printing temperature was 160 ℃ and the rest of the procedure was the same as in preparation example 1.

As a result: the printing is carried out to obtain a light yellow transparent round tablet which has glossy surface, good appearance and larger hardness.

Test example 1: prescription and technological research (1)

The preparation process was as described in preparation example 1.

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％

As a result:

the results show that formulations 1-1, 1-2, 1-3 can be successfully printed into sheets, while formulations 1-4, 1-5 cannot be successfully printed due to uneven melt extrusion, because the amount of acetaminophen that can be carried by the hot melt matrix Kollidon VA64 is limited due to excessive drug loading during printing, and therefore, the results show that Kollidon VA64 can carry acetaminophen at a maximum drug loading of about 35%.

2. Effect of plasticizers on printing

As shown in table 2 below.

TABLE 2

The results are shown in Table 3 below.

TABLE 3

Prescription	Printing temperature (. degree.C.)	Appearance of the product
			2-1	150	Milky white round tablet
2-2	145	Milky round tablets, slight collapse
			2-3	135	Milky round tablets with pronounced collapse
2-4	155	Milky white round tablet
			2-5	147	Milky round tablets with pronounced collapse
2-6	142	Milky round tablets with pronounced collapse
			2-7	152	Milky white round tablet
2-8	156	Milky white round tablet

The results show that:

after adding poloxamer 407, the printing temperature is reduced, and with the increase of the addition amount, the temperature is reduced more, and the formed molten material is softer, but the addition amount is too much, so that the material is too soft to make the tablet collapse;

the formulation with 5% of plasticizer PEG6000 added gives tablets with good appearance, and when added to 5% or more, the tablets collapse, but the formulation with PEG6000 added has a higher printing temperature than that with poloxamer 407 added, so that under the condition of ensuring both low temperature and appearance, the preferred solution is that poloxamer 407 is added in an amount of 5%.

The stability of the material can be further ensured by reducing the printing temperature, the toughness of the extruded material can be increased, the brittleness can be reduced, and the printing can be carried out more easily. If poloxamer 407 is not added, extrusion is not possible at low temperatures.

3. Effect of disintegrants on printing

As shown in table 4 below.

TABLE 4

The results are shown in Table 5 below.

TABLE 5

Prescription	Printing temperature (. degree.C.)	Appearance of the product
			3-1	155	Milky white round tablet
3-2	160	Milky white round tablet
			3-3	170	Milky white round tablet
3-4	185	Yellow round tablet
			3-5	/	Failure of printing
3-6	/	Failure of printing

The results show that the tablets can still be printed after addition of the disintegrant Kollidon cl-F, but the printing temperature is increased, and the temperature increase is more pronounced the greater the amount added, and the printing temperature is increased to 185 ℃ when the amount added reaches 25%, at which point the printed tablets turn yellow. The material itself is light yellow, but the darkening of yellow indicates to some extent that the material has undergone some change, which is preferably discarded. Therefore, the disintegrant Kollidon cl-F is added in an amount of at most 20%.

After the disintegrating agents CMS-Na and CCNa are added, the printing temperature and various parameters can not be printed after being adjusted, the material is extruded discontinuously, and cannot be formed, which indicates that the two disintegrating agents can not be used as hot-melt printing addition materials in the formula.

Test example 2: in vitro Release assay (1)

The preparation process of each formulation was as described in preparation example 1.

The dissolution method is shown in table 6 below.

TABLE 6

Dissolution method	Paddle method
		Dissolution media	Hydrochloric acid of pH1.2
Volume of medium	900ml
		Dissolution temperature	37℃
Rotational speed	50rpm
		Number of cups	6 cup

4. 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

	Dissolution rate of 0.5h	Dissolution rate of 1h	Dissolution rate of 3h
				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％

As a result: the results show that the addition of the disintegrant Kollidon cl-F under the experimental conditions has no accelerating effect on the dissolution of the tablet and rather slows down the dissolution rate, indicating that the disintegrant Kollidon cl-F can not play a role in promoting the dissolution of the drug under the hot-melt extrusion conditions. It is known to those skilled in the art that disintegrants generally increase the dissolution rate, but do not play a corresponding role here.

5. Effect of line spacing on in vitro Release

As shown in table 9 below.

TABLE 9

The results are shown in Table 10 below.

Watch 10

As a result: the results show that the in vitro release speeds of the tablets with different line spacing are obviously different, the dissolution is faster as the line spacing is larger, the tablets with three different line spacing can complete different release, and the tablets can be used as sustained release tablets to complete release within 3 hours in the stomach when the line spacing is 0.7 or 0.9 mm; when the distance between the threads is 1.1mm, the tablet can be used as a common tablet, and the release rate in the stomach is more than 80% within 1 h.

Test example 3: prescription and technological research (2)

6. Drug loading study

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％

As a result:

the results show that formulations 6-1, 6-2, 6-3 can be successfully printed into sheets, while formulations 6-4, 6-5 cannot be successfully printed due to uneven melt extrusion, since the amount of acetaminophen that the hot melt matrix soluplus can carry during printing is limited due to excessive drug loading, and therefore, the maximum drug loading of acetaminophen that the soluplus can carry is about 40%.

7. Effect of plasticizers 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.

Watch 13

As in preparation example 1, the printing temperature was lowered by adding poloxamer 407, and the lower the temperature the more the amount was added, the softer the extruded molten material, changing the appearance of the tablet from yellowish transparent to yellowish opaque. However, the addition of too much poloxamer 407 in the printed tablet with soluplus as hot melt matrix resulted in the tablet being too soft to collapse and difficult to align, so poloxamer 407 was added in an amount of 5%.

8. Effect of disintegrants on printing

As shown in table 14 below.

TABLE 14

The results are shown in Table 15 below.

Watch 15

Prescription	Printing temperature (. degree.C.)	Appearance of the product
			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	/	Failure of printing
8-6	/	Failure of printing

The printing can be successfully carried out after 10 percent of Kollidoncl-F is added, the temperature is lower, the color and the appearance of the tablet are better, the printing temperature is obviously increased and the color of the tablet is darkened by adding 20 percent or more of Kollidon cl-F, and the low temperature is favorable for the thermal stability of the material and the darkening of the color is questioned whether the degradation occurs or not and generally discarded. In addition, the addition of CMS-Na and CCNa did not result in successful printing, which was characterized by non-uniform extrusion of the melt (non-uniform thickness) and no formation.

Test example 4: in vitro Release assay (2)

Dissolution method

As shown in table 16 below.

TABLE 16

Dissolution method	Paddle method
		Dissolution media	pH6.8 phosphate buffer
Volume of medium	900ml
		Dissolution temperature	37℃
Rotational speed	50rpm
		Number of cups	6 cup

9. Effect 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.

Watch 18

	Dissolution rate of 0.5h	Dissolution rate of 3h	Dissolution rate of 12h	Dissolution rate of 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 acetaminophen printed tablets based on soluplus promotes faster dissolution of the tablets, the in vitro release of the tablets increases with increasing addition of Kollidon cl-F, and the dissolution behavior changes, the tablets with addition of Kollidon cl-F of less than 20% dissolve in an erosion type, while the tablets with addition of 20% disintegrant disintegrate, release both by erosion and disintegration. The two methods have no good or bad difference, and whether the dissolution rate can meet the requirement is mainly determined.

In addition, the dissolution in stomach is usually faster due to gastric emptying (the united states pharmacopeia requires 3h to 80%), while the dissolution in intestine can be prolonged due to the long retention time of the medicine in intestine, and the dissolution form and dissolution time can be adjusted by different materials and proportions.

10. Effect of line spacing on in vitro Release

As shown in table 19 below.

Watch 19

The results are shown in Table 20 below.

Watch 20

	Dissolution rate of 0.5h	Dissolution rate of 3h	Dissolution rate of 12h	Dissolution rate of 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 the soluble plus based tablets have different fluff promoting speeds at different line intervals with the same prescription, the dissolution is faster when the line interval is larger, and the 12h dissolution rate is more than 80% when the line interval is 1.1mm, so that good dissolution in intestinal tracts can be completed.

Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Various modifications and substitutions of those details may be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims

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

the acetaminophen slow-release preparation is prepared by a preparation method comprising the following steps: mixing the components, and performing 3D printing by a hot melt extrusion molding technology;

wherein,

the hot-melt extrusion matrix is selected from one or more of copovidone and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer;

the plasticizer is one or more selected from poloxamer 407 and PEG6000, and when the plasticizer contains the poloxamer 407, the weight percentage content is 3% -10%; when the PEG6000 is contained, the content of the weight percent is 3 percent to 5 percent;

the disintegrant is Kollidon cl-F, and the weight percentage content of the disintegrant is less than or equal to 20 percent;

the line spacing of 3D printing is 0.7-0.9 mm;

the printing temperature for 3D printing is 145-175 ℃.

2. An acetaminophen sustained release formulation as claimed in claim 1 wherein the copovidone is Kollidon VA 64.

3. The acetaminophen controlled-release formulation of claim 1, wherein the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is Soluplus.

4. An acetaminophen sustained release formulation as claimed in any one of claims 1 to 3 wherein,

the plasticizer further comprises triethyl citrate.

5. An acetaminophen controlled release formulation as claimed in any one of claims 1 to 3 comprising the following components:

6. an acetaminophen controlled release formulation as claimed in any one of claims 1 to 3 comprising the following components:

acetaminophen 175-200 weight portions

Kollidon VA 64175-300 weight parts

40720-30 parts by weight of poloxamer.

7. The extended release paracetamol formulation according to claim 6, wherein the poloxamer 407 is present in an amount of 25 parts by weight.

8. An acetaminophen controlled release formulation as claimed in any one of claims 1 to 3 comprising the following components:

acetaminophen 175 weight part

Kollidon VA 64300 parts by weight

40720-30 parts by weight of poloxamer.

9. The extended release paracetamol formulation according to claim 8, wherein the poloxamer 407 is present in an amount of 25 parts by weight.

10. An acetaminophen controlled release formulation as claimed in any one of claims 1 to 3 comprising the following components:

11. the extended release paracetamol formulation according to claim 10, wherein the poloxamer 407 is present in an amount of 25 parts by weight.

12. An acetaminophen controlled release formulation as claimed in any one of claims 1 to 3 comprising the following components:

13. the extended release paracetamol formulation according to claim 12, wherein the poloxamer 407 is present in an amount of 25 parts by weight.

14. An acetaminophen sustained release formulation as claimed in any one of claims 1 to 3 which is an acetaminophen sustained release tablet.

15. The acetaminophen controlled-release formulation of claim 1, wherein the printing temperature for 3D printing is 145-155 ℃.

16. An acetaminophen sustained release formulation as claimed in claim 1 wherein the printing temperature for 3D printing is from 150 ℃ to 175 ℃.

17. An acetaminophen controlled-release formulation as claimed in claim 1 wherein the printing temperature for 3D printing is 150-155 ℃.

18. An acetaminophen sustained release formulation as claimed in claim 1 wherein the printing temperature for 3D printing is from 155 ℃ to 175 ℃.

19. An acetaminophen controlled-release formulation as claimed in any one of claims 1 to 4 wherein the 3D printed layer height is 0.6-0.8 mm.

20. An acetaminophen sustained release formulation as claimed in claim 19 wherein the 3D printed layer height is 0.7 mm.