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

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 printed loratadine orally disintegrating tablet and its raw material composition and preparation method

technical field

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

Background technique

Currently available loratadine tablets are prepared by traditional tableting methods. There are two specifications: 10mg and 5mg, of which 10mg is suitable for people over 12 years old, and 5mg is suitable for people aged 2 to 12 years old.

However, with the development of precision medical technology, higher requirements are placed on the treatment plan. Not only the treatment method should be adjusted according to the patient's condition, the type of medication and treatment strategy should be adjusted, but also the dosage should be adjusted according to the patient's condition. Adjusted for individual differences such as body weight.

However, at present, conventional loratadine tablets are all given dosage specifications, and it is impossible to adjust the effective dose of each tablet according to individual differences such as patient weight.

SUMMARY OF THE INVENTION

Based on this, it is necessary to provide a raw material composition for 3D printing loratadine orally disintegrating tablets in view of the above problems. The active dose of loratadine can be adjusted flexibly to meet the needs of preparing loratadine oral disintegrating tablets with different body weights and different dosage requirements.

A composition for 3D printing loratadine orally disintegrating tablets, which is composed of a solid component and a liquid component, and the solid component is mainly composed of the following raw materials by mass:

The liquid component is a polyvinylpyrrolidone solution, and the dosage ratio of the solid component to the liquid component is 1000g solid component:1600±160ml liquid component.

The above-mentioned composition for 3D printing loratadine orally disintegrating tablets can be directly used in semi-solid extrusion 3D printing equipment, using the characteristics of rapid prototyping and digital modeling of 3D printing technology, and giving full play to 3D printing technology in the production of individual products. According to the advantages of customized and customized pharmaceutical preparations, loratadine orally disintegrating tablets of corresponding specifications are customized according to the patient's weight, so that the patient's dosage is more accurate and the adverse drug reactions are reduced; the tablet can also be customized according to the patient's taste to improve the Compliance of patients, especially children.

In one embodiment, the polyvinylpyrrolidone is PVP K30.

In one embodiment, the polyvinylpyrrolidone solution is an aqueous solution of polyvinylpyrrolidone of 6±0.6g/100ml. And using water as a solvent can not only reduce the use of organic solvents, avoid the problem of solvent residues, but also ensure that the semi-solid mixture in the syringe is not easy to dry and block during the extrusion molding process of the preparation.

In one embodiment, the amount of the sodium carboxymethyl starch used accounts for 10±1 wt % of the total solid content.

In one embodiment, the mass ratio of the mannitol to the ethyl cellulose is 0.5:(1±0.1).

The invention also discloses the above-mentioned preparation method of the composition for 3D printing loratadine orally disintegrating tablets, comprising the following steps:

Weigh loratadine, ethyl cellulose and sodium carboxymethyl starch according to the prescribed amount, mix well, add polyvinylpyrrolidone solution, grind to a semi-solid state, add mannitol, and then add flavoring agents as needed, grind Evenly, that is.

The invention also discloses a preparation method of 3D printing loratadine orally disintegrating tablets, comprising the following steps:

Take the above-mentioned raw material composition for 3D printing loratadine orally disintegrating tablets, put it into a syringe, print the tablet in a semi-solid extrusion 3D printer, and dry it.

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

The inventors found in the previous research that loratadine is a strong hydrophobic drug and is not easily wetted by water. By using ordinary 3D printing technology, through the selection and adjustment of prescriptions and excipients, its disintegration time limit is still difficult to meet the requirements. After repeated conditional exploration and experimental screening, it was found that the formulation could be designed into a grid shape, thereby improving the disintegration time limit, and the orally disintegrating tablet could disintegrate smoothly within the disintegration time limit specified in the Pharmacopoeia.

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

The invention also discloses loratadine orally disintegrating tablets prepared by the above-mentioned preparation method of 3D printing loratadine orally disintegrating tablets.

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

The composition for 3D printing loratadine orally disintegrating tablets of the present invention can be directly used in semi-solid extrusion 3D printing equipment, and 3D printing loratadine of corresponding specifications can be customized according to individual needs such as patient weight. Oral disintegrating tablets can make the patient's dosage more accurate and reduce adverse drug reactions; tablets can also be customized according to the patient's taste to improve the compliance of patients, especially children.

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

Description of drawings

Fig. 1 is a photo of orally disintegrating tablet obtained by screening and obtaining the optimal prescription and process in Example 1.

Detailed ways

In order to facilitate understanding of the present invention, the present invention will be described more fully hereinafter with reference to the related drawings. Preferred embodiments of the invention are shown in the accompanying drawings. However, the present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that a thorough and complete understanding of the present disclosure is provided.

Unless otherwise defined, 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 terms used herein in the description of the present invention are for the purpose of describing specific embodiments only, and are not intended to limit the present invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

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

Example 1

Screening of formulation and preparation technology of loratadine orally disintegrating tablets.

1. Screening of adhesive models

1. Method.

Weigh loratadine, ethyl cellulose, and sodium carboxymethyl starch (CMS-Na) according to the following different recipe quantities, mix well, add PVP aqueous solutions with a concentration of 6% by mass and volume of different molecular weights, and grind them into In a semi-solid state, add mannitol and grind it evenly, and optionally add or not add a flavoring agent (in this example, no flavoring agent is added), to obtain a raw material combination for 3D printing loratadine orally disintegrating tablets thing.

The above-mentioned semi-solid composition is loaded into a syringe, and cylindrical tablets are printed in a semi-solid extrusion 3D printer (Prose Technology, Shenzhen, seven-medical), and dried at room temperature to obtain 3D printed loratadine. Disintegrate.

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

The 3D printed loratadine orally disintegrating tablets obtained above (6 tablets per prescription) were tested according to the method of "Chinese Pharmacopoeia" (2020 edition), and the average disintegration time limit was tested.

2. Results.

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

Table 1. Screening of Adhesive Models

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 nature Not easy to extrude Easy extrusion Easy extrusion Average disintegration time (s) N 69 >4min

Note: N means that due to the nature of the prescription, it is not suitable for 3D printing, and the final test was not printed.

The results showed that both PVP K30 and PVP K88 were suitable for 3D printing, and finally PVP K30 was selected as the binder according to the disintegration time limit of orally disintegrating tablets in the Chinese Pharmacopoeia.

2. Screening of adhesive ratio

1. Method.

According to the following different prescriptions and referring to the method in step 1, 3D printed loratadine orally disintegrating tablets were prepared.

2. Results.

Referring to the above-mentioned disintegration time determination method, four ratios of PVP K30 were screened, and the results were 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 nature not easy to form poor forming easy to form easy to form Average disintegration time (s) N 56 69 160

The results show that as the proportion of PVP K30 increases, the formability of the semi-solid composition becomes better, but the average disintegration time is prolonged. Considering several factors such as formability and disintegration time, 6% PVP K30 was selected as the binder.

3. Screening of disintegrant dosage

1. Method.

According to the following different prescriptions and referring to the method in step 1, 3D printed loratadine orally disintegrating tablets were prepared.

2. Results.

With reference to the above-mentioned disintegration time determination method, four proportions of disintegrant CMS-Na are screened, and the results are shown in the following table.

Table 3. The ratio of each excipient

Note: The above % refers to the mass percentage of the excipients in the solid content.

Table 4. The dosage of each excipient

In the above table, table 3 is the ratio between each adjuvant, and table 4 is the adjuvant consumption of final feeding after conversion according to the ratio, first according to the ratio of loratadine and CMS-Na accounting for the whole solid mixture, determine the quality of the two, The rest is ethyl cellulose and mannitol, and the mass of the two is determined according to the ratio of the two.

The results show that as the proportion of CMS-Na increases, the amount of binder needs to be increased, so that the semi-solid composition has better fluidity and viscosity, and can be extruded. The consumption of the mixture also increased correspondingly, the average disintegration time limit changed little, and the consumption of CMS-Na was selected as 10%.

4. Screening of mannitol ratio (mannitol: ethyl cellulose)

1. Method.

According to the following different prescriptions and referring to the method in step 1, 3D printed loratadine orally disintegrating tablets were prepared.

2. Results.

Referring to the above-mentioned disintegration time determination method, four ratios of mannitol: ethyl cellulose are screened, and the results are shown in the following table.

Table 5. The dosage of each excipient

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 nature Hard, hard to squeeze easy to form easy to form easy to block Average disintegration time (s) N 69 86.5 N

The results showed that four kinds of carbitol ratio (0, 0.5:1, 1:1, 1.5:1) were screened, and 0.5:1 was selected according to the comprehensive consideration of semi-solid composition and disintegration time limit.

5. Selection of filling rate of grid-shaped tablets

1. Method.

Weigh 3 g of loratadine, 4 g of ethyl cellulose, and 1 g of sodium carboxymethyl starch, mix well, add 16 ml of 6% PVP K30, grind to a semi-solid state, add 2 g of mannitol, grind well, and put it into a syringe , print a cylindrical tablet in a semi-solid extrusion 3D printer, and dry it at room temperature.

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

2. Results.

With reference to the above-mentioned disintegration time measurement method, the four grid filling ratios were screened, and considering that the grid printing method may have an impact on the friability of the obtained tablets, the friability was also determined according to the Pharmacopoeia. The evaluation results are shown in the table below.

Table 6. Fill Rate Screening Results

prescription 1 prescription 2 prescription 3 prescription 4 Fill rate (%) 100 80 60 40 Tablet weight (mg) 89.15 70.52 48.90 27.72 Average disintegration time (s) 69 52 30 18 Friability (%) 0.4 0.5 0.7 0.9

By screening the four filling rates, the results show that with the decrease of the filling rate, the disintegration time is gradually shortened, which meets the requirement of the disintegration time for the orally disintegrating tablet in the Pharmacopoeia to be less than 60s; with the decrease of the filling rate, the friability gradually decreases. get bigger. Therefore, considering the requirements of tablet weight, disintegration time and friability, the filling rate of the tablet is 60%.

6. Prescription screening results.

After various adjustments and screening of prescriptions, the inventors found that, because loratadine is a strong hydrophobic drug, it still fails to meet the requirements for the disintegration time limit of orally disintegrating tablets in the Chinese Pharmacopoeia after prescription screening. The tablet is designed as a grid, which increases the contact area between the tablet and the medium, and can shorten the disintegration time of the tablet to meet the requirements of the preparation.

The optimal semi-solid composition for 3D printing loratadine orally disintegrating tablets was finally determined as follows: loratadine 3g, ethyl cellulose 4g, sodium carboxymethyl starch 1g, 6% PVP K30 16ml, mannitol 2g.

The optimal process conditions for obtaining orally disintegrating tablets by printing with the above semi-solid composition are: nozzle diameter 0.6mm, extrusion line width 0.6mm, layer height 0.6mm, filling pattern is linear, filling rate 60%, printing speed 6mm/ s.

The photo of the loratadine orally disintegrating tablet obtained by the above method is shown in Figure 1.

Example 2

A 3D printed loratadine orally disintegrating tablet (specification: 5mg), prepared by the following method:

Weigh 3 g of micronized loratadine, 4 g of ethyl cellulose, and 1 g of sodium carboxymethyl starch, mix well, add 16 ml of 6% polyvinylpyrrolidone (PVPK30) solution, grind to a semi-solid state, add 2 g of mannitol Grind evenly, then add 0.1 g of flavoring agent and grind to obtain a semi-solid composition.

The above-mentioned semi-solid composition was put into a syringe and printed in a semi-solid extrusion type 3D printer according to the following parameters.

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

By adopting the above method, loratadine orally disintegrating tablets with a specification of 5 mg can be prepared and dried at room temperature.

Example 3

A 3D printed loratadine orally disintegrating tablet (specification: 7mg), prepared by the following method:

Weigh 3 g of micronized loratadine, 4 g of ethyl cellulose, and 1 g of sodium carboxymethyl starch, mix well, add 16 ml of 6% polyvinylpyrrolidone (PVPK30) solution, grind to a semi-solid state, add 2 g of mannitol Grind evenly, then add 0.1 g of flavoring agent and grind to obtain a semi-solid composition.

The above-mentioned semi-solid composition was put into a syringe and printed in a semi-solid extrusion type 3D printer according to the following parameters.

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

By adopting the above method, loratadine orally disintegrating tablets with a specification of 7 mg can be prepared and dried at room temperature.

Example 4

Application of a customized loratadine orally disintegrating tablet.

1. Used in hospital pharmacies

A 2.5-year-old child, female, weighing 15kg, has allergic rhinitis. The doctor prescribed oral loratadine 2.6mg once a day.

The hospital pharmacy filled the pre-prepared semi-solid composition for 3D printing loratadine orally disintegrating tablets into a syringe, and the semi-solid extrusion 3D printer entered the tablet size (long diameter) according to the loratadine dose. 4mm, short diameter 4mm, height 1.8mm) according to the preset parameters to print out the required grid-shaped tablets, and dry at room temperature.

The above pre-produced loratadine 3D printing semi-solid composition prescription is: loratadine 300g, ethyl cellulose 400g, carboxymethyl starch sodium 100g, 6% polyvinylpyrrolidone (PVPK30) 1600ml, mannitol 200g, 10g of flavoring agent and grind well.

The 3D printing parameters are as follows: the shape is cylindrical, the nozzle diameter 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 6mm/s.

2. For social pharmacy

An 11-year-old boy, weighing 41kg, has allergic rhinitis. The child should take 7mg of the drug once a day.

The patient's family members can buy it at the social pharmacy, and the social pharmacy will put the pre-prepared semi-solid composition for 3D printing loratadine orally disintegrating tablets into the syringe, and the semi-solid extrusion 3D printer will print it according to the loratadine. Enter the tablet size at a fixed dose (length diameter 8mm, short diameter 6mm, height 2.4mm) and print out the required grid-shaped tablets according to the preset parameters, and dry at room temperature.

The above pre-produced loratadine 3D printing semi-solid composition prescription is: loratadine 300g, ethyl cellulose 400g, carboxymethyl starch sodium 100g, 6% polyvinylpyrrolidone (PVPK30) 1600ml, mannitol 200g, 10g of flavoring agent and grind well.

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%, and the printing speed is 6mm/s.

The formulation is a custom-made tablet that does not require long-distance transportation. According to the Chinese Pharmacopoeia (2020 edition) tablet friability test method, the friability of the preparation was checked.

The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity, all possible combinations of the technical features in the above-described embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, All should be regarded as the scope described in this specification.

The above-mentioned embodiments only represent several embodiments of the present invention, and the descriptions thereof are more specific and detailed, but should not be construed as a limitation on the scope of the invention patent. It should be pointed out that for those skilled in the art, without departing from the concept of the present invention, several modifications and improvements can be made, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the appended claims.

Claims (2)

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 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 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.

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