CN112043676B

CN112043676B - 3D printing loratadine orally disintegrating tablet and raw material composition and preparation method thereof

Info

Publication number: CN112043676B
Application number: CN202011130197.2A
Authority: CN
Inventors: 易少凌; 陈伶俐; 余泽君; 吴泽鹏
Original assignee: Guangdong Food and Drugs Vocational College
Current assignee: Gecko Medical Technology Shanghai Co ltd
Priority date: 2020-10-21
Filing date: 2020-10-21
Publication date: 2022-07-12
Anticipated expiration: 2040-10-21
Also published as: CN112043676A

Abstract

The invention relates to a 3D printed loratadine orally disintegrating tablet, and raw materials and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. The composition comprises a solid component and a liquid component, wherein the solid component mainly comprises the following raw materials in parts by mass: 300 plus or minus 30 parts of loratadine, 400 plus or minus 40 parts of ethyl cellulose, 100 plus or minus 10 parts of sodium carboxymethyl starch, 200 plus or minus 10 parts of mannitol and 0-10 parts of flavoring agent. The liquid component is polyvinylpyrrolidone solution, and the dosage ratio of the solid component to the liquid component is 1000g of solid component to 1600 plus or minus 160ml of liquid component. The composition is used for 3D printing to obtain the loratadine orally disintegrating tablet, and the active dosage of loratadine can be flexibly adjusted to adapt to the preparation of the loratadine orally disintegrating tablets with different weights and different dosage requirements. And the customized loratadine orally disintegrating tablet has the advantages of simple preparation method, easy operation and wide application.

Description

3D printing loratadine orally disintegrating tablet and raw material composition and preparation method thereof

Technical Field

The invention relates to the technical field of pharmaceutical preparations, in particular to a 3D printing loratadine orally disintegrating tablet, a raw material composition and a preparation method thereof.

Background

Currently, commercially available loratadine tablets are prepared by a traditional tabletting method, and have two specifications: 10mg and 5mg, wherein 10mg is suitable for people over 12 years old, and 5mg is suitable for people 2-12 years old.

However, with the development of precise medical technology, higher requirements are put on treatment schemes, and not only the treatment mode, the type and strategy of medication should be adjusted according to the disease condition of the patient, but also the dosage should be adjusted according to individual differences such as the weight of the patient.

However, the conventional loratadine tablets have given dosage specifications, and the effective dose of each tablet cannot be adjusted according to individual difference conditions such as the weight of a patient.

Disclosure of Invention

Based on the above, there is a need to provide a raw material composition for 3D printing of loratadine orally disintegrating tablets, which is a semi-solid raw material for customizing loratadine orally disintegrating tablets in a 3D printing manner, and can flexibly adjust the active dosage of loratadine to meet the requirements of preparing loratadine orally disintegrating tablets with different weights and dosage requirements.

The composition for 3D printing of the loratadine orally disintegrating tablet comprises a solid component and a liquid component, wherein the solid component mainly comprises the following raw materials in parts by mass:

the liquid component is polyvinylpyrrolidone solution, and the dosage ratio of the solid component to the liquid component is 1000g of solid component to 1600 +/-160 ml of liquid component.

The composition for 3D printing of the loratadine orally disintegrating tablets can be directly used in semisolid extrusion type 3D printing equipment, the advantages of the 3D printing technology in the aspects of producing individualized and customized medicine preparations are exerted by the characteristics of rapid forming and digital modeling of the 3D printing technology, and the loratadine orally disintegrating tablets with corresponding specifications are customized according to the weight of a patient, so that the dosage of the patient is more accurate, and the adverse reaction of the medicine is reduced; the tablets may also be customized to the patient's taste, improving patient compliance, particularly in pediatric patients.

In one embodiment, the polyvinylpyrrolidone is PVP K30.

In one embodiment, the polyvinylpyrrolidone solution is a 6 ± 0.6g/100ml aqueous solution of polyvinylpyrrolidone. And water is used as a solvent, so that the use of organic solvents can be reduced, the problem of solvent residue is avoided, and the semi-solid mixture in the injector is not easy to dry and block in the preparation extrusion molding process.

In one embodiment, the sodium carboxymethyl starch is used in an amount of 10 ± 1 wt% based on the total amount of the solid components.

In one embodiment, the mass ratio of the mannitol to the ethylcellulose is 0.5 (1. + -. 0.1).

The invention also discloses a preparation method of the composition for 3D printing of the loratadine orally disintegrating tablet, which comprises the following steps:

weighing loratadine, ethyl cellulose and sodium carboxymethyl starch according to the formula amount, uniformly mixing, adding a polyvinylpyrrolidone solution, uniformly grinding to be in a semisolid state, adding mannitol, adding a flavoring agent according to needs, and uniformly grinding to obtain the loratadine-containing oral liquid.

The invention also discloses a preparation method of the 3D printed loratadine orally disintegrating tablet, which comprises the following steps:

and (3) loading the raw material composition for 3D printing of the loratadine orally disintegrating tablet into an injector, printing the tablet in a semisolid extrusion type 3D printer, and drying to obtain the loratadine orally disintegrating tablet.

In one embodiment, 3D printing is performed according to the following parameter conditions: and printing in a grid-shaped printing mode, wherein the filling rate of the grid-shaped printing mode is 60 +/-6%.

The inventor finds in earlier researches that loratadine is a strong hydrophobic drug and is not easy to wet by water, common 3D printing technology is adopted, the disintegration time limit still cannot meet the requirement through screening and adjusting of a prescription and auxiliary materials, and then repeated condition exploration and experimental screening find that the preparation can be designed into a grid shape, so that the disintegration time limit is improved, and the oral disintegrating tablet can be disintegrated smoothly within the disintegration time limit specified by pharmacopoeia.

In one embodiment, 3D printing is performed according to the following parameter conditions: the diameter of the nozzle is 0.6 plus or minus 0.1mm, the extrusion line width is 0.6 plus or minus 0.1mm, the layer height is 0.6 plus or minus 0.1mm, the filling pattern is linear, and the printing speed is 6 plus or minus 1 mm/s.

The invention also discloses a loratadine orally disintegrating tablet prepared by the preparation method of the 3D printed loratadine orally disintegrating tablet.

Compared with the prior art, the invention has the following beneficial effects:

the composition for 3D printing of the loratadine orally disintegrating tablet can be directly used in semisolid extrusion type 3D printing equipment, and the 3D printing loratadine orally disintegrating tablet with the corresponding specification can be customized according to the individual requirements of the weight and the like of a patient, so that the dosage of the patient is more accurate, and the adverse reaction of the medicine is reduced; the tablets may also be customized to the patient's taste, improving patient compliance, particularly in pediatric patients.

And the preparation method of the 3D printed loratadine orally disintegrating tablet is simple, easy to operate and easy to popularize and use.

Drawings

FIG. 1 is a photograph of an orally disintegrating tablet obtained by the screening for the optimum prescription and process in example 1.

Detailed Description

To facilitate an understanding of the invention, the invention will now be described more fully with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

The starting materials used in the following examples are all commercially available unless otherwise specified.

Example 1

The loratadine orally disintegrating tablet prescription and the preparation process thereof are screened.

Screening of adhesive types

1. A method is provided.

Weighing loratadine, ethyl cellulose and sodium carboxymethyl starch (CMS-Na) according to the following different prescription amounts, uniformly mixing, adding PVP aqueous solution with different molecular weights and 6% of mass volume percentage concentration, uniformly grinding to be in a semisolid state, adding mannitol, uniformly grinding, and optionally adding or not adding a flavoring agent (the flavoring agent is not added in the embodiment) according to needs to obtain the raw material composition for the 3D printing loratadine orally disintegrating tablets.

And (3) filling the semisolid composition into an injector, printing a cylindrical tablet in a semisolid extrusion type 3D printer (Sanwen science and technology, Shenzhen, seven-medical), and drying at normal temperature to obtain the 3D printed loratadine orally disintegrating tablet.

3D printing parameters: cylindrical, 8mm in diameter and 2.4mm high; the diameter of the nozzle is 0.6mm, the extrusion line width is 0.6mm, the layer height is 0.6mm, the filling pattern is linear, the filling rate is 100%, and the printing speed is 6 mm/s.

The 3D printed loratadine orally disintegrating tablets (6 tablets are selected per prescription) obtained above are tested for average disintegration time according to the method of Chinese pharmacopoeia (2020 edition).

2. And (4) obtaining the result.

Three molecular weight PVPs were screened and the results are shown in the table below.

TABLE 1 screening of adhesive types

	Prescription 1	Prescription 2	Prescription 3
				Loratadine (g)	1.5	1.5	1.5
Mannitol (g)	1	1	1
				Ethyl cellulose (g)	2	2	2
CMS-Na(g)	0.5	0.5	0.5
				6％PVP K16(ml)	8	-	-
6％PVP K30(ml)	-	8	-
				6％PVP K88(ml)	-	-	8
Properties of	Is not easy to extrude and form	Easy extrusion molding	Easy extrusion molding
				Mean disintegration time limit(s)	N	69	>4min

Note: n indicates that 3D printing is not appropriate due to the nature of the prescription and finally unprinted test.

The results show that both PVP K30 and PVP K88 are suitable for 3D printing, and finally PVP K30 is selected as a binder according to the disintegration time limit requirements of orally disintegrating tablets in the chinese pharmacopoeia.

Second, screening of the proportion of the adhesive

1. A method.

According to the following different prescriptions, the 3D printing loratadine orally disintegrating tablet is prepared by referring to the method in the step one.

2. And (6) obtaining the result.

Four ratios of PVP K30 were screened according to the disintegration time measurement method described above, and the results are shown in the following table.

TABLE 2 screening of binder ratios

	Prescription 1	Prescription 2	Prescription 3	Prescription 4
					Loratadine (g)	1.5	1.5	1.5	1.5
Mannitol (g)	1	1	1	1
					Ethyl cellulose (g)	2	2	2	2
CMS-Na(g)	0.5	0.5	0.5	0.5
					2％PVP K30(ml)	8	-	-	-
4％PVP K30(m^l)	-	8	-	-
					6％PVP K30(ml)	-	-	8	-
8％PVP K30(ml)	-	-	-	8
					Properties of	Is not easy to form	Poor formation	Easy to form	Easy to form
Mean disintegration time limit(s)	N	56	69	160

The results show that the semi-solid composition becomes better in formability as the proportion of PVP K30 increases, but the average disintegration time period is prolonged. In consideration of several factors such as formability, disintegration time and the like, PVP K30 with the concentration of 6% is selected as the adhesive.

Thirdly, screening the dosage of the disintegrating agent

1. A method.

According to different prescriptions, the 3D printed loratadine orally disintegrating tablet is prepared by referring to the method in the step one.

2. And (4) obtaining the result.

Four proportions of the disintegrant CMS-Na were screened according to the disintegration time measurement method described above, and the results are shown in the following table.

TABLE 3 proportions of the adjuvants

Note: the above% refers to the mass percentage of the auxiliary material in the solid component.

TABLE 4 dosage of each adjuvant

In the table above, table 3 shows the ratio of each auxiliary material, table 4 shows the amount of the auxiliary material finally fed according to the ratio conversion, the mass of loratadine and CMS-Na is determined according to the ratio of loratadine to CMS-Na in the whole solid mixture, the mass of ethylcellulose and mannitol is left, and the mass of loratadine and CMS-Na is determined according to the ratio of loratadine to CMS-Na.

The results show that as the proportion of CMS-Na increases, the amount of binder needs to be increased to obtain a semi-solid composition with better flowability and viscosity for extrusion, and therefore as the proportion of disintegrant increases, the amount of binder increases accordingly, with little change in the mean disintegration time, with a CMS-Na content of 10% being chosen.

Screening of mannitol and ethyl cellulose

1. A method.

2. And (6) obtaining the result.

With reference to the above disintegration time measurement method, for four ratios of mannitol: the results of the screening of ethylcellulose are shown in the following table.

TABLE 5 dosage of each adjuvant

	Prescription 1	Prescription 2	Prescription 3	Prescription 4
					Loratadine (g)	1.5	1.5	1.5	1.5
Mannitol (g)	0	1	1.5	1.8
					Ethyl cellulose (g)	3	2	1.5	1.2
CMS-Na(g)	0.5	0.5	0.5	0.5
					6％PVP K30(ml)	8	8	8	8
Properties of	Hard and difficult to extrude	Easy to form	Easy to form	Easy to block
					Mean disintegration time limit(s)	N	69	86.5	N

The results show that four glycine to glycine ratios (0, 0.5:1, 1:1, 1.5:1) were screened and the glycine to glycine ratio was selected to be 0.5:1 based on a combination of the semi-solid composition and the disintegration time period.

Fifthly, selection of filling rate of grid-shaped tablets

1. A method.

Weighing 3g of loratadine, 4g of ethyl cellulose and 1g of sodium carboxymethyl starch, uniformly mixing, adding 6% PVP K3016 ml, uniformly grinding to be in a semisolid state, adding 2g of mannitol, uniformly grinding, filling into an injector, printing a cylindrical tablet in a semisolid extrusion type 3D printer, and drying at normal temperature to obtain the loratadine-containing tablet.

3D printing parameters: cylindrical, 8mm in diameter and 2.4mm high; the diameter of the nozzle is 0.6mm, the extrusion line width is 0.6mm, the layer height is 0.6mm, the filling pattern is linear, the filling rate is shown in the following table, and the printing speed is 6 mm/s.

2. And (6) obtaining the result.

The four mesh filling rates were screened in accordance with the disintegration time measuring method described above, and the friability was evaluated in accordance with the pharmacopoeia regulations at the same time, considering that the use of the mesh printing method may affect the friability of the resulting tablets, and the results are shown in the following table.

TABLE 6 Filler Rate screening results

	Prescription 1	Prescription 2	Prescription 3	Prescription 4
					Filling ratio (%)	100	80	60	40
Tablet weight (mg)	89.15	70.52	48.90	27.72
					Mean disintegration time limit(s)	69	52	30	18
Friability (%)	0.4	0.5	0.7	0.9

The results of screening the four filling rates show that the disintegration time limit is gradually shortened along with the reduction of the filling rate, and the requirement of the oral disintegration tablet on the disintegration time limit being less than 60s in pharmacopoeia is met; as the filling rate decreases, the friability becomes gradually larger. Therefore, the filling ratio of the tablet is selected to be 60% in consideration of the requirements of the tablet weight, disintegration time and friability.

Sixthly, screening results of the prescription.

The inventor discovers that after a plurality of adjustment and screening of the prescription, the requirement of orally disintegrating tablets on disintegration time limit in Chinese pharmacopoeia can not be met after the prescription screening is carried out because loratadine is a strong hydrophobic drug, and the disintegration time limit of the tablets can be shortened by designing the tablets into a grid shape and increasing the contact area between the tablets and a medium so as to meet the requirement of the preparation.

The optimal formulation of the semisolid composition for 3D printing of loratadine orally disintegrating tablets was finally determined as: 3g of loratadine, 4g of ethyl cellulose, 1g of sodium carboxymethyl starch, 6% of PVP K3016 ml and 2g of mannitol.

The optimal process conditions for obtaining the orally disintegrating tablet by matching with the semisolid composition are as follows: the diameter of the nozzle is 0.6mm, the extrusion line width is 0.6mm, the layer height is 0.6mm, the filling pattern is linear, the filling rate is 60%, and the printing speed is 6 mm/s.

A photograph of the orally disintegrating tablet of loratadine obtained in the above manner is shown in FIG. 1.

Example 2

A3D printed loratadine orally disintegrating tablet (specification: 5mg) is prepared by the following method:

weighing 3g of micronized loratadine, 4g of ethyl cellulose and 1g of sodium carboxymethyl starch, uniformly mixing, adding 16ml of 6% polyvinylpyrrolidone (PVPK30) solution, uniformly grinding to be in a semisolid state, adding 2g of mannitol, uniformly grinding, adding 0.1g of flavoring agent, and uniformly grinding to obtain the semisolid composition.

The semisolid composition was filled into a syringe and printed in a semisolid extrusion type 3D printer under the following parameter conditions.

Printing parameters: the shape is cylindrical, the long diameter is 8mm, the short diameter is 4mm, and the height is 2.4 mm; the diameter of the nozzle is 0.6mm, the extrusion line width is 0.6mm, the layer height is 0.6mm, the filling pattern is linear, the filling rate is 60 percent, and the printing speed is 6 mm/s.

By adopting the method, the loratadine orally disintegrating tablet with the specification of 5mg can be prepared and dried at normal temperature, and the loratadine orally disintegrating tablet is obtained.

Example 3

A3D printed loratadine orally disintegrating tablet (specification: 7mg) is prepared by the following method:

The semisolid composition was put into a syringe, and printing was performed in a semisolid extrusion type 3D printer under the following parameter conditions.

Printing parameters: the shape is cylindrical, the long diameter is 8mm, the short diameter is 6mm, and the height is 2.4 mm; the diameter of the nozzle is 0.6mm, the extrusion line width is 0.6mm, the layer height is 0.6mm, the filling pattern is linear, the filling rate is 60 percent, and the printing speed is 6 mm/s.

By adopting the method, the loratadine orally disintegrating tablet with the specification of 7mg can be prepared and dried at normal temperature, and the loratadine orally disintegrating tablet is obtained.

Example 4

An application of a customized loratadine orally disintegrating tablet.

1. Used in hospital pharmacy

A child is 2.5 years old, a woman has a weight of 15kg, allergic rhinitis is treated by a doctor orally taking 2.6mg of loratadine once a day.

And (3) filling the pre-prepared semisolid composition for 3D printing of the loratadine orally disintegrating tablet into a syringe by a hospital pharmacy, printing a latticed tablet with required specifications according to preset parameters by a semisolid extrusion type 3D printer according to the size (the long diameter is 4mm, the short diameter is 4mm, and the height is 1.8mm) of the loratadine input tablet, and drying at normal temperature to obtain the loratadine orally disintegrating tablet.

The formula of the pre-produced loratadine 3D printing semisolid composition comprises the following components: 300g of loratadine, 400g of ethyl cellulose, 100g of sodium carboxymethyl starch, 1600ml of 6% polyvinylpyrrolidone (PVPK30), 200g of mannitol and 10g of flavoring agent are ground uniformly.

The 3D printing parameters are as follows: the shape is cylindrical, the diameter of the nozzle is 0.6mm, the extrusion line width is 0.6mm, the layer height is 0.6mm, the filling pattern is linear, the filling rate is 60 percent, and the printing speed is 6 mm/s.

2. For social pharmacy

A child 11 years old, male, body weight 41kg, allergic rhinitis, and children should take the medicine 7mg orally once a day.

The patient family members can purchase the composition from a social pharmacy, the social pharmacy puts a pre-prepared semisolid composition for 3D printing of the loratadine orally disintegrating tablet into a syringe, a semisolid extrusion type 3D printer prints a latticed tablet with required specifications according to preset parameters according to the size (the long diameter is 8mm, the short diameter is 6mm and the height is 2.4mm) of the loratadine dosage input tablet, and the loratadine orally disintegrating tablet is obtained after drying at normal temperature.

3D printing parameters: the shape is cylindrical, the diameter of the nozzle is 0.6mm, the extrusion line width is 0.6mm, the layer height is 0.6mm, the filling pattern is linear, the filling rate is 60 percent, and the printing speed is 6 mm/s.

The preparation is a customized tablet, and does not need long-distance transportation. The friability of the preparation is checked according to a tablet friability checking method in Chinese pharmacopoeia (2020 edition), and the friability of the preparation accords with the specification of the pharmacopoeia, which indicates that the preparation can meet the short-distance distribution condition.

All possible combinations of the technical features of the above embodiments may not be described for the sake of brevity, but should be considered as within the scope of the present disclosure as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. A preparation method of a 3D printed loratadine orally disintegrating tablet is characterized by comprising the following steps:

taking the composition for 3D printing of the loratadine orally disintegrating tablet, filling the composition into an injector, printing the tablet in a semisolid extrusion type 3D printer, and drying to obtain the loratadine orally disintegrating tablet;

the liquid component is polyvinylpyrrolidone solution, and the dosage ratio of the solid component to the liquid component is 1000g of solid component and 1600 plus or minus 160ml of liquid component;

the polyvinylpyrrolidone is PVP K30;

the polyvinylpyrrolidone solution is a polyvinylpyrrolidone aqueous solution with the concentration of 6 plus or minus 0.6g/100 ml;

the amount of the sodium carboxymethyl starch accounts for 10 +/-1 wt% of the total amount of the solid components;

the mass ratio of the mannitol to the ethyl cellulose is 0.5 (1 +/-0.1);

the preparation method of the composition comprises the following steps:

weighing loratadine, ethyl cellulose and sodium carboxymethyl starch according to the formula amount, uniformly mixing, adding a polyvinylpyrrolidone solution, uniformly grinding to be in a semisolid state, adding mannitol, adding a flavoring agent according to needs, and uniformly grinding to obtain the loratadine-containing oral liquid;

the 3D printing loratadine orally disintegrating tablet is subjected to 3D printing according to the following parameter conditions: printing by adopting a grid-shaped printing mode, wherein the filling rate of the grid-shaped printing mode is 60 +/-6%;

the diameter of the nozzle is 0.6 plus or minus 0.1mm, the extrusion line width is 0.6 plus or minus 0.1mm, the layer height is 0.6 plus or minus 0.1mm, the filling pattern is linear, and the printing speed is 6 plus or minus 1 mm/s.

2. The loratadine orally disintegrating tablet prepared by the preparation method of 3D printing loratadine orally disintegrating tablet of claim 1.