CN116270505A - Oral solid preparation containing lasmidbody hemisuccinate and 3D printing preparation technology thereof - Google Patents

Oral solid preparation containing lasmidbody hemisuccinate and 3D printing preparation technology thereof Download PDF

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CN116270505A
CN116270505A CN202111559311.8A CN202111559311A CN116270505A CN 116270505 A CN116270505 A CN 116270505A CN 202111559311 A CN202111559311 A CN 202111559311A CN 116270505 A CN116270505 A CN 116270505A
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hemisuccinate
printing
oral solid
percent
solid preparation
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苏梅
金龙
代孔恩
李彦玲
张孝清
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Nanjing Comer Biomedical Co ltd
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Nanjing Comer Biomedical Co ltd
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Abstract

The invention belongs to the field of pharmaceutical preparations, and in particular relates to an oral solid preparation containing lasmiptan hemisuccinate and a 3D printing preparation method thereof, wherein the oral solid preparation comprises lasmiptan hemisuccinate as a main drug, and auxiliary materials such as a filler, a disintegrating agent, an adhesive, a cosolvent, a flavoring agent and a lubricant, wherein the lasmiptan hemisuccinate has a particle size D 90 The preparation process of the oral solid preparation is not more than 20 mu m, and adopts a 3D printing technology. The oral solid preparation disclosed by the invention has the advantages of uniform content, rapid disintegration, complete release within 5 minutes and timely effect taking, can be completely disintegrated within 60 seconds, has no gritty feel after being orally taken, and greatly increases the bioavailability. The oral solid preparation is prepared by adopting a 3D printing technology at the front edge of the field, no special auxiliary materials are needed, and good operability of the production technology and stability of a finished product can be ensured.

Description

Oral solid preparation containing lasmidbody hemisuccinate and 3D printing preparation technology thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a lasmidbody hemisuccinate oral solid preparation and a 3D printing preparation technology thereof.
Background
The chemical name of the Lasmiditan hemisuccinate (Lasmiditan) is 2,4, 6-trifluoro-N- [6- [ (1-methyl-4-piperidinyl) carbonyl ] -2-pyridinyl ] benzamide, and the chemical structure is as follows:
Figure 727490DEST_PATH_IMAGE001
the lasmidbody hemisuccinate is a 5-hydroxytryptamine 1F receptor antagonist with high affinity and has a unique action mechanism. It is the first and only FDA approved new pharmaceutical formulation for acute migraine treatment for 20 years, and its efficacy may be exerted by antagonism of the target receptor.
The results of cloning of the human 5-hydroxytryptamine subtype 1F (5-HT 1F) receptor by Synthctic Biometrics in the United states, gift (Eli Lilly and Company) Inc. at 3, 2003, were first developed. The american gift company (Eli Lilly and Company) submitted a new drug to the FDA for marketing on 14 11 2018 and was approved for marketing on 11 10 2019. The trade name of the lamidian hemisuccinate tablet is Reyvow. Lamidian is an oral, central nervous system penetrating, selective, 5-HT1F agonist with a mechanism of action different from the new drugs currently available in bulk for the treatment of migraine, without vasoconstrictor effect, and safer for migraine patients suffering from or at risk of cardiovascular disease.
The lamidian hemisuccinate tablet is obtained in the FDA batch at 10 months 11 of 2019, and has the trade name of Reyvow, the manufacturer of the tablet is Eli Lilly and Company, and the specification of 50mg,100mg and 200mg. At present, the lamidian hemisuccinate tablet has no original grinding import and no original grinding generation.
The original american gift (Eli Lilly and Company) company discloses in the product Reyvow cube an oral pharmaceutical combination comprising lasmidbody hemisuccinate. The pharmaceutical combination comprises the active ingredients: lasmiptan hemisuccinate; inactive ingredients: crosslinked sodium carboxymethyl cellulose, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium dodecyl sulfate; coating components: iron oxide, polyethylene glycol, polyvinyl alcohol, talcum powder and titanium dioxide. The comparative study shows that the existing laslmidian hemisuccinate tablet sold in the market abroad has slower disintegration rate and poorer collapse effect.
Disclosure of Invention
The invention aims to overcome the defects of long disintegration time, poor stability and poor disintegrating effect of the existing product, and provides an oral solid preparation containing the lasmiptan hemisuccinate, which can not only rapidly disintegrate, but also well mask the bitter tingling of the lasmiptan hemisuccinate and increase the stability of the oral solid preparation.
Another object of the present invention is to provide a 3D printing preparation method of the above solid formulation.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
the invention provides an oral solid preparation containing the lasmiptan hemisuccinate, which comprises the lasmiptan hemisuccinate serving as a main medicine, and auxiliary materials including a filler, a disintegrating agent, an adhesive, a cosolvent, a flavoring agent, a preservative, a lubricant, a wetting agent and a colorant, wherein the main medicine and the auxiliary materials comprise the following components in percentage by weight: lawset hemisuccinate5.0 to 10.0 percent of mildipitant, 70.0 to 85.0 percent of filler, 1.0 to 6.0 percent of disintegrating agent, 1.0 to 6.0 percent of adhesive, 1.0 to 3.0 percent of cosolvent, 0.5 to 2.5 percent of flavoring agent, 0.1 to 2.0 percent of preservative, 0.5 to 2.0 percent of lubricant, 0.1 to 2.0 percent of wetting agent and 0.1 to 1.0 percent of colorant; the research shows that the particle size of the lasmidbody hemisuccinate affects the mixing uniformity and the in-vitro release rate of the product, and the particle size D of the lasmidbody hemisuccinate ensures the mixing uniformity and the in-vitro release rate 90 The particle size range of the raw materials can be controlled by adopting technologies such as crushing, grinding and the like. According to an embodiment of the invention, the particle size D of the lasmidbody hemisuccinate 90 Preferably not greater than 20 μm.
The oral solid preparation containing the lasmidbody hemisuccinate contains a filler in a certain proportion, and the filler has a good pore structure, so that the lasmidbody hemisuccinate after being micronized can be adsorbed in the pore structure, and the mixing uniformity is ensured. The filler has the advantages of good disintegration, taste, fluidity and the like, and can greatly improve the qualification rate of the tablets in the production process. The prepared oral solid preparation of the laslmidian hemisuccinate has good disintegration effect, and can be rapidly disintegrated after a patient takes the medicine to release active substances so as to enable a human body to rapidly absorb the active substances. According to an embodiment of the invention, the filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, starch; in order to improve the problems of poor disintegrating and sand-flickering of the commercially available orally disintegrating tablets, researches show that microcrystalline cellulose is selected as a filler, so that the dosage of the filler is reduced, and the taking taste and the formability are ensured. According to an embodiment of the invention, the filler is preferably derived from microcrystalline cellulose.
According to an embodiment of the present invention, the disintegrating agent is selected from one or more of croscarmellose sodium, crospovidone, and sodium carboxymethyl starch; sodium croscarmellose is preferred.
According to an embodiment of the present invention, the binder is one or more selected from povidone, pregelatinized starch, hydroxypropyl cellulose, hypromellose; pregelatinized starch is preferred.
According to the embodiment of the invention, the cosolvent is one or more selected from Tween 80 and sodium dodecyl sulfate; sodium dodecyl sulfate is preferred.
According to the embodiment of the invention, the flavoring agent is one or more selected from sucrose, aspartame, saccharin sodium, steviosin and peppermint essence; steviosin and/or peppermint essence are preferred.
According to the embodiment of the invention, the preservative is selected from one or more of methylparaben, sodium benzoate, chlorobutanol and benzalkonium chloride; methyl hydroxybenzoate is preferred.
According to an embodiment of the present invention, the lubricant is one or more selected from soybean oil, almond oil, olive oil, rapeseed oil, and coconut oil; soybean oil is preferred.
According to the embodiment of the invention, the wetting agent is one or more selected from glycerol, propylene glycol and polyethylene glycol; glycerol is preferred.
According to an embodiment of the invention, the coloring agent is one or more selected from lemon yellow, carmine, indigo and curcumin; indigo is preferred.
The invention also provides a preparation method of the oral solid preparation containing the lasmidbody hemisuccinate, which comprises the following steps:
(a) The lasmiditant hemisuccinate is subjected to airflow micronization treatment, and the particle size range is controlled to be D 90 Not more than 20 μm;
(b) Mixing the treated lasmiditant hemisuccinate with a filler in a certain proportion in a hopper mixer, and sieving after fully mixing;
(c) Adding disintegrating agent, adhesive, cosolvent, correctant and colorant into the obtained Lasmid-filler mixed powder, and mixing in hopper mixer to obtain powder component of 3D printing semisolid material;
(d) Dissolving a required amount of preservative into a certain amount of solvent, and then adding a required amount of wetting agent into the solvent to uniformly mix the components to prepare a liquid component of the 3D printing semisolid material;
(e) The oil phase component of the 3D printing semisolid material is a lubricant;
(g) Adding the required amount of powder components into the liquid components, uniformly mixing the powder components, adding the oil phase components into the liquid components, and uniformly mixing the oil phase components to prepare the 3D printing semisolid material;
(h) Filling the semisolid material, and sealing and preserving an aluminum bag;
(i) Filling semisolid materials containing the medicinal active ingredients into a 3D printer, and preserving heat;
(j) The semisolid material in the injector is extruded downwards by controlling a printer charging barrel screw through 3D printing software, and after extrusion, the semisolid material is deposited on a 3D printing platform;
(k) The printer controls a printing path according to the generated g code, extrudes semisolid materials layer by layer, and forms corresponding patterns on a 3D printing platform;
(l) And (5) after drying, packaging.
Compared with the prior art, the invention has the beneficial effects that:
1) The oral solid preparation containing the lasmifene hemisuccinate, which is prepared by the invention, has uniform content and rapid disintegration, can be completely disintegrated within 60 seconds, can be completely released within 5 minutes, can timely take effect, has no gritty feel after being orally taken, and greatly increases the bioavailability.
2) The preparation process of the 3D printing preparation provided by the invention overturns the design and production mode of the traditional preparation, can realize personalized customization of medicines, improves the production efficiency of the preparation, controls the release rate of medicines, increases the compliance of patients, and accelerates the progress of digital medical revolution.
Drawings
FIG. 1 is a graph showing the particle size distribution of the lamivudine hemisuccinate according to the present invention.
FIG. 2 is a graph comparing dissolution data of examples of the present invention with comparative examples in hydrochloric acid solution at pH 1.2.
FIG. 3 is a graph comparing dissolution data in acetate buffer at pH4.5 for examples of the present invention and comparative examples.
FIG. 4 is a graph comparing dissolution data in acetate buffer at pH6.8 for examples of the present invention and comparative examples.
FIG. 5 is a graph comparing dissolution data in water for examples of the present invention and comparative examples.
FIG. 6 is a graph comparing dissolution curves of examples and comparative examples of the present invention.
FIG. 7 is a graph showing the trend of the degradation of impurities under accelerated conditions in examples and comparative examples according to the present invention.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
Experimental materials: lactose (mexiletan), microcrystalline cellulose (Anhui Shanhe pharmaceutical excipients Co., ltd.), mannitol (Luo Gaite), croscarmellose sodium (DuPont), crospovidone (DuPont), povidone (Chongqing Qingyang pharmaceutical Co., ltd.), povidone (Guizhou Xin Zihong pharmaceutical excipients Co., ltd.), pregelatinized starch (Henan Zheng pharmaceutical excipients Co., ltd.), hydroxypropyl cellulose (Japan Caddy Co., ltd.), tween 80 (Hubei Kudzuvine human excipients Co., ltd.), sodium dodecyl sulfate (Hunan Hongyang pharmaceutical Co., ltd.), aspartame (Hunan Jiujiujiuzhen pharmaceutical excipients Co., ltd.), steviosin (Hunan Korea pharmaceutical excipients Co., ltd.), peppermint essence (American forest pigment Co., ltd.), hydroxybenzoate (Jiangxi Gao Kong Co., ltd.), soybean oil (Hunan Kagao Co., ltd.), glycerin (European Litsea Co., ltd.), and Revom.35 Revom.
Experimental facilities: electronic balance (Metrele-Topsido international trade (Shanghai), laboratory jet mill (Kunshan Qiangwei powder equipment Co., ltd.), hopper mixer (Zhejiang brand mechanical technology Co., ltd.), 3D printer (3D Systems), laser particle sizer (European Topseizer), and dissolution instrument (Shenzhen Sharp instrument Co., ltd RT 612).
The detection method comprises the following steps: the dissolution rate and dissolution curve measuring method adopts the method of measuring the dissolution rate and the release rate of 4 parts 0931 of Chinese pharmacopoeia 2020 edition under the item of measuring method.
Example 1
1. Prescription of prescription
Figure 910209DEST_PATH_IMAGE002
2. Preparation method
(1) And (3) raw material treatment: the lasmidbody hemisuccinate is micronized to the granularity D 90 Not more than 20 μm;
(2) active ingredient-filler blend: adding the prescription amount of the laslmidian hemisuccinate, mannitol and microcrystalline cellulose into a mixer, and uniformly mixing;
(3) mixing powder components: adding the active ingredient-filler mixed powder, crosslinked sodium carboxymethylcellulose, pregelatinized starch, sodium dodecyl sulfate, steviosin, peppermint essence and indigo into a mixer, and uniformly mixing;
(4) preparing a liquid component: dissolving the prescription amount of methylparaben in a certain amount of water, adding the prescription amount of glycerin, and uniformly mixing;
(5) preparing a semi-solid material: adding the powder component into the liquid component to uniformly disperse the powder component, adding the prescription amount of soybean oil into the liquid component to uniformly mix the powder component and the soybean oil, filling the semisolid material, and sealing and preserving the semisolid material by an aluminum bag;
(6) 3D printing: filling semisolid material containing the medicinal active ingredient into a 3D printer, and preserving heat. And controlling a printer charging barrel screw to downwards extrude the semisolid material in the injector through 3D printing software, and depositing the semisolid material on a 3D printing platform after extrusion. And the printer controls the printing path according to the generated g codes, extrudes the semisolid materials layer by layer, forms corresponding patterns on the 3D printing platform, and dries.
Example 2
1. Prescription of prescription
Figure 830892DEST_PATH_IMAGE003
2. Preparation method
(1) And (3) raw material treatment: the lasmidbody hemisuccinate is micronized to the granularity D 90 Not more than 20 μm;
(2) active ingredient-filler blend: adding the prescription amount of the masculine hemisuccinate, mannitol and lactose into a mixer for uniform mixing;
(3) mixing powder components: adding the active ingredient-filler mixed powder, crosslinked sodium carboxymethylcellulose, pregelatinized starch, sodium dodecyl sulfate, steviosin, peppermint essence and indigo into a mixer, and uniformly mixing;
(4) preparing a liquid component: dissolving the prescription amount of methylparaben in a certain amount of water, adding the prescription amount of glycerin, and uniformly mixing;
(5) preparing a semi-solid material: adding the powder component into the liquid component to uniformly disperse the powder component, and then adding the prescription amount of soybean oil into the liquid component to uniformly mix the powder component and the liquid component;
(6) 3D printing: filling semisolid material containing the medicinal active ingredient into a 3D printer, and preserving heat. And controlling a printer charging barrel screw to downwards extrude the semisolid material in the injector through 3D printing software, and depositing the semisolid material on a 3D printing platform after extrusion. And the printer controls the printing path according to the generated g codes, extrudes the semisolid materials layer by layer, forms corresponding patterns on the 3D printing platform, and dries.
Example 3
1. Prescription of prescription
Figure 491680DEST_PATH_IMAGE004
2. Preparation method
(1) And (3) raw material treatment: the lasmidbody hemisuccinate is micronized to the granularity D 90 Not more than 20 μm;
(2) active ingredient-filler blend: adding the prescription amount of the laslmidian hemisuccinate and the microcrystalline cellulose into a mixer for uniform mixing;
(3) mixing powder components: adding the active ingredient-filler mixed powder, crosslinked sodium carboxymethylcellulose, pregelatinized starch, sodium dodecyl sulfate, steviosin, peppermint essence and indigo into a mixer, and uniformly mixing;
(4) preparing a liquid component: dissolving the prescription amount of methylparaben in a certain amount of water, adding the prescription amount of glycerin, and uniformly mixing;
(5) preparing a semi-solid material: adding the powder component into the liquid component to uniformly disperse the powder component, and then adding the prescription amount of soybean oil into the liquid component to uniformly mix the powder component and the liquid component;
(6) 3D printing: filling semisolid material containing the medicinal active ingredient into a 3D printer, and preserving heat. And controlling a printer charging barrel screw to downwards extrude the semisolid material in the injector through 3D printing software, and depositing the semisolid material on a 3D printing platform after extrusion. And the printer controls the printing path according to the generated g codes, extrudes the semisolid materials layer by layer, forms corresponding patterns on the 3D printing platform, and dries.
Example 4
1. Prescription of prescription
Figure 571632DEST_PATH_IMAGE005
2. Preparation method
(1) And (3) raw material treatment: the lasmidbody hemisuccinate is micronized to the granularity D 90 Not more than 20 μm;
(2) active ingredient-filler blend: adding the prescription amount of the masculine hemisuccinate and lactose into a mixer for uniform mixing;
(3) mixing powder components: adding the active ingredient-filler mixed powder, crosslinked sodium carboxymethylcellulose, pregelatinized starch, sodium dodecyl sulfate, steviosin, peppermint essence and indigo into a mixer, and uniformly mixing;
(4) preparing a liquid component: dissolving the prescription amount of methylparaben in a certain amount of water, adding the prescription amount of glycerin, and uniformly mixing;
(5) preparing a semi-solid material: adding the powder component into the liquid component to uniformly disperse the powder component, and then adding the prescription amount of soybean oil into the liquid component to uniformly mix the powder component and the liquid component;
(6) 3D printing: filling semisolid material containing the medicinal active ingredient into a 3D printer, and preserving heat. And controlling a printer charging barrel screw to downwards extrude the semisolid material in the injector through 3D printing software, and depositing the semisolid material on a 3D printing platform after extrusion. And the printer controls the printing path according to the generated g codes, extrudes the semisolid materials layer by layer, forms corresponding patterns on the 3D printing platform, and dries.
Example 5
1. Prescription of prescription
Figure 800619DEST_PATH_IMAGE006
2. Preparation method
(1) And (3) raw material treatment: the lasmidbody hemisuccinate is micronized to the granularity D 90 Not more than 20 μm;
(2) active ingredient-filler blend: adding the prescription amount of the laslmidian hemisuccinate and the microcrystalline cellulose into a mixer for uniform mixing;
(3) mixing powder components: adding the active ingredient-filler mixed powder, crosslinked povidone, pregelatinized starch, sodium dodecyl sulfate, aspartame, peppermint essence and indigo into a mixer, and uniformly mixing;
(4) preparing a liquid component: dissolving the prescription amount of methylparaben in a certain amount of water, adding the prescription amount of glycerin, and uniformly mixing;
(5) preparing a semi-solid material: adding the powder component into the liquid component to uniformly disperse the powder component, and then adding the prescription amount of soybean oil into the liquid component to uniformly mix the powder component and the liquid component;
(6) 3D printing: filling semisolid material containing the medicinal active ingredient into a 3D printer, and preserving heat. And controlling a printer charging barrel screw to downwards extrude the semisolid material in the injector through 3D printing software, and depositing the semisolid material on a 3D printing platform after extrusion. And the printer controls the printing path according to the generated g codes, extrudes the semisolid materials layer by layer, forms corresponding patterns on the 3D printing platform, and dries.
Example 6
1. Prescription of prescription
Figure 333232DEST_PATH_IMAGE007
2. Preparation method
(1) And (3) raw material treatment: the lasmidbody hemisuccinate is micronized to the granularity D 90 Not more than 20 μm;
(2) active ingredient-filler blend: adding the prescription amount of the laslmidian hemisuccinate and the microcrystalline cellulose into a mixer for uniform mixing;
(3) mixing powder components: adding active ingredient-filler mixed powder, sodium carboxymethyl starch, pregelatinized starch, sodium dodecyl sulfate, aspartame, peppermint essence and indigo into a mixer, and mixing uniformly;
(4) preparing a liquid component: dissolving the prescription amount of methylparaben in a certain amount of water, adding the prescription amount of glycerin, and uniformly mixing;
(5) preparing a semi-solid material: adding the powder component into the liquid component to uniformly disperse the powder component, and then adding the prescription amount of soybean oil into the liquid component to uniformly mix the powder component and the liquid component;
(6) 3D printing: filling semisolid material containing the medicinal active ingredient into a 3D printer, and preserving heat. And controlling a printer charging barrel screw to downwards extrude the semisolid material in the injector through 3D printing software, and depositing the semisolid material on a 3D printing platform after extrusion. And the printer controls the printing path according to the generated g codes, extrudes the semisolid materials layer by layer, forms corresponding patterns on the 3D printing platform, and dries.
Example 7
1. Prescription of prescription
Figure 797711DEST_PATH_IMAGE008
2. Preparation method
(1) And (3) raw material treatment: the lasmidbody hemisuccinate is micronized to the granularity D 90 Not more than 20 μm;
(2) active ingredient-filler blend: adding the prescription amount of the laslmidian hemisuccinate and the microcrystalline cellulose into a mixer for uniform mixing;
(3) mixing powder components: adding the active ingredient-filler mixed powder, crosslinked sodium carboxymethylcellulose, hydroxypropyl cellulose, sodium dodecyl sulfate, aspartame, peppermint essence and indigo into a mixer, and uniformly mixing;
(4) preparing a liquid component: dissolving the prescription amount of methylparaben in a certain amount of water, adding the prescription amount of glycerin, and uniformly mixing;
(5) preparing a semi-solid material: adding the powder component into the liquid component to uniformly disperse the powder component, and then adding the prescription amount of soybean oil into the liquid component to uniformly mix the powder component and the liquid component;
(6) 3D printing: filling semisolid material containing the medicinal active ingredient into a 3D printer, and preserving heat. And controlling a printer charging barrel screw to downwards extrude the semisolid material in the injector through 3D printing software, and depositing the semisolid material on a 3D printing platform after extrusion. And the printer controls the printing path according to the generated g codes, extrudes the semisolid materials layer by layer, forms corresponding patterns on the 3D printing platform, and dries.
Example 8
1. Prescription of prescription
Figure 873114DEST_PATH_IMAGE009
2. Preparation method
(1) And (3) raw material treatment: the lasmidbody hemisuccinate is micronized to the granularity D 90 Not more than 20 μm;
(2) active ingredient-filler blend: adding the prescription amount of the laslmidian hemisuccinate and the microcrystalline cellulose into a mixer for uniform mixing;
(3) mixing powder components: adding the active ingredient-filler mixed powder, croscarmellose sodium, povidone, sodium dodecyl sulfate, aspartame, peppermint essence and indigo into a mixer, and uniformly mixing;
(4) preparing a liquid component: dissolving the prescription amount of methylparaben in a certain amount of water, adding the prescription amount of glycerin, and uniformly mixing;
(5) preparing a semi-solid material: adding the powder component into the liquid component to uniformly disperse the powder component, and then adding the prescription amount of soybean oil into the liquid component to uniformly mix the powder component and the liquid component;
(6) 3D printing: filling semisolid material containing the medicinal active ingredient into a 3D printer, and preserving heat. And controlling a printer charging barrel screw to downwards extrude the semisolid material in the injector through 3D printing software, and depositing the semisolid material on a 3D printing platform after extrusion. And the printer controls the printing path according to the generated g codes, extrudes the semisolid materials layer by layer, forms corresponding patterns on the 3D printing platform, and dries.
Example 9
1. Prescription of prescription
Figure 132057DEST_PATH_IMAGE010
2. Preparation method
(1) And (3) raw material treatment: the lasmidbody hemisuccinate is micronized to the granularity D 90 Not more than 20 μm;
(2) active ingredient-filler blend: adding the prescription amount of the laslmidian hemisuccinate and the microcrystalline cellulose into a mixer for uniform mixing;
(3) mixing powder components: adding the active ingredient-filler mixed powder, crosslinked sodium carboxymethylcellulose, povidone, steviosin, peppermint essence and indigo into a mixer, and uniformly mixing;
(4) preparing a liquid component: dissolving Tween 80 and methylparaben in a certain amount of water, adding glycerol in a certain amount, and mixing uniformly;
(5) preparing a semi-solid material: adding the powder component into the liquid component to uniformly disperse the powder component, and then adding the prescription amount of soybean oil into the liquid component to uniformly mix the powder component and the liquid component;
(6) 3D printing: filling semisolid material containing the medicinal active ingredient into a 3D printer, and preserving heat. And controlling a printer charging barrel screw to downwards extrude the semisolid material in the injector through 3D printing software, and depositing the semisolid material on a 3D printing platform after extrusion. And the printer controls the printing path according to the generated g codes, extrudes the semisolid materials layer by layer, forms corresponding patterns on the 3D printing platform, and dries.
Example 10
1. Prescription of prescription
Figure 151966DEST_PATH_IMAGE011
2. Preparation method
(1) And (3) raw material treatment: the lasmidbody hemisuccinate is micronized to the granularity D 90 At 20-50 μm;
(2) active ingredient-filler blend: adding the prescription amount of the laslmidian hemisuccinate and the microcrystalline cellulose into a mixer for uniform mixing;
(3) mixing powder components: adding the active ingredient-filler mixed powder, crosslinked sodium carboxymethylcellulose, pregelatinized starch, sodium dodecyl sulfate, steviosin, peppermint essence and indigo into a mixer, and uniformly mixing;
(4) preparing a liquid component: dissolving the prescription amount of methylparaben in a certain amount of water, adding the prescription amount of glycerin, and uniformly mixing;
(5) preparing a semi-solid material: adding the powder component into the liquid component to uniformly disperse the powder component, and then adding the prescription amount of soybean oil into the liquid component to uniformly mix the powder component and the liquid component;
(6) 3D printing: filling semisolid material containing the medicinal active ingredient into a 3D printer, and preserving heat. And controlling a printer charging barrel screw to downwards extrude the semisolid material in the injector through 3D printing software, and depositing the semisolid material on a 3D printing platform after extrusion. And the printer controls the printing path according to the generated g codes, extrudes the semisolid materials layer by layer, forms corresponding patterns on the 3D printing platform, and dries.
Comparative example 1
The product is prepared from the raw materials of the lamivudine hemisuccinate, and has the trade name of Reyvow, the specification of 50mg, the evidence-holding manufacturer of Eli Lilly and Companyc and the drugs on the market in the United states.
Test example 1
The mixing uniformity is measured, and the measuring method of the mixing uniformity comprises the following steps: after the mixing of the hopper mixer is finished, the materials are respectively sampled at 7 different positions (an upper layer middle part, an upper layer wall attaching part, a middle layer front part, a middle layer middle part, a middle layer lower part, a lower layer middle part and a lower layer wall attaching part) in the hopper, the content is measured, and the RSD at the different positions is calculated to be not more than 5%.
The mixing uniformity judgment standard is that RSD is less than or equal to 3 percent and is regarded as excellent, RSD is less than or equal to 5 percent and is regarded as qualified, and RSD is more than 5 percent and is regarded as unqualified.
The measurement results of the above test examples are shown in Table 1.
TABLE 1 mixing uniformity RSD measurement results
Figure 154557DEST_PATH_IMAGE012
"-" indicates that the corresponding parameter is not detected.
Test example 2
Determination of disintegration time, determination method of disintegration time: and placing the prepared tablet in a culture dish containing 2mL of purified water at 37 ℃, visually observing the disintegration of the tablet until the hard core is not seen, and recording the disintegration time, namely the disintegration time, and measuring the diameter of the bottom surface of the material pile after the complete disintegration, so as to evaluate the collapse effect of the tablet. The vessel was gently shaken and then the solution was poured onto a 30 mesh stainless steel screen, and no substantial residue on the screen was considered acceptable for gritty feel after disintegration of the orally disintegrating tablet. The 6 pieces were repeatedly measured, and the above examples and comparative examples were measured, and the test results are shown in the following table:
table 2 disintegration time measurement results
Figure 818888DEST_PATH_IMAGE013
Examples 1-10 all had better disintegration times and degree of disintegration than comparative example 1. Among them, examples 1 to 4 and examples 7 to 9 had more excellent disintegration time and degree of disintegration. The examples have the same or even shorter disintegration time and better disintegration effect than the reference formulation compared to comparative example 1.
Test example 3
Dissolution rate comparison dissolution rate measurements were performed on examples 1 to 10 and comparative example 1. Experimental method according to the dissolution assay, 0.1N hydrochloric acid solution, ph6.8 phosphate buffer, ph4.5 acetate buffer, aqueous medium, volume 900m, rotation speed 50rpm, n=12, sampling time point 3 minutes were selected. The results were as follows:
table 3 comparison of dissolution rates of examples and comparative examples
Figure 514311DEST_PATH_IMAGE014
As can be seen from Table 3, the samples of examples 1-10 in different dissolution media all had better dissolution rates within 3 minutes than comparative example 1.
Test example 4
Dissolution profile measurements were performed for examples 1-10 and comparative example 1. Experimental method according to the dissolution rate measurement method, phosphate buffer medium with pH of 6.8 was selected, the volume was 900ml, the rotation speed was 50rpm, n=12, and samples were taken at 5, 10, 15, 20 and 30 minutes, respectively, to determine the cumulative dissolution rate. The results were as follows:
table 4 comparison of dissolution curves for examples and comparative examples
Figure 21516DEST_PATH_IMAGE015
As can be seen from Table 4, the samples of examples 1-10 had better cumulative dissolution rates than comparative example 1 in phosphate buffer medium at pH6.8 for the first 15 minutes.
Test example 5
Stability comparison samples of inventive examples 1-10 and comparative example 1 were taken and placed under accelerated conditions (40 ℃ + -2 ℃/75% RH+ -5% RH) for preliminary stability investigation.
Table 5 stability comparison
Figure 703164DEST_PATH_IMAGE016
The samples prepared in examples 1-10 showed comparable tendencies to increase in impurity under accelerated conditions as compared to comparative example 1, and the samples prepared in examples 1-10 showed comparable stability as compared to the reference formulation.

Claims (7)

1. The oral solid preparation containing the lasmiptan hemisuccinate is characterized by comprising the main drug lasmiptan hemisuccinate, auxiliary materials including fillers, disintegrants, adhesives, cosolvent, flavoring agents, preservatives, lubricants, wetting agents and colorants, wherein the main drug and the auxiliary materials comprise the following components in percentage by weight: 5.0 to 10.0 percent of lasmidbody hemisuccinate, 70.0 to 85.0 percent of filler, 1.0 to 6.0 percent of disintegrating agent, 1.0 to 6.0 percent of adhesive, 1.0 to 3.0 percent of cosolvent, 0.5 to 2.5 percent of flavoring agent, 0.1 to 2.0 percent of preservative, 0.5 to 2.0 percent of lubricant, 0.1 to 2.0 percent of wetting agent and 0.1 to 1.0 percent of colorant.
2. The oral solid preparation containing the lasmiptan hemisuccinate according to claim 1, wherein the particle size range D90 of the lasmiptan hemisuccinate in the oral solid preparation containing the lasmiptan hemisuccinate is not more than 20 μm.
3. An oral solid formulation comprising lasmidbody hemisuccinate according to claim 1, wherein said filler is selected from the group consisting of: microcrystalline cellulose, lactose, mannitol, starch.
4. An oral solid preparation comprising lasmidbody hemisuccinate according to claim 3, wherein said filler is selected from microcrystalline cellulose.
5. An oral solid formulation comprising lasmiptan hemisuccinate according to claim 1, wherein said disintegrant is selected from the group consisting of: one or more of croscarmellose sodium, crospovidone and sodium carboxymethyl starch;
the adhesive is selected from the group consisting of: one or more of povidone, pregelatinized starch, hydroxypropyl cellulose and hypromellose;
the cosolvent is selected from the group consisting of: tween 80, one or more of sodium dodecyl sulfate;
the flavoring agent is selected from the group consisting of: sucrose, aspartame, saccharin sodium, steviosin, and peppermint essence;
the preservative is selected from the group consisting of: one or more of methylparaben, sodium benzoate, chlorobutanol and benzalkonium chloride;
the lubricant is selected from the group consisting of: one or more of soybean oil, almond oil, olive oil, rapeseed oil and coconut oil;
the wetting agent is selected from the group consisting of: one or more of glycerol, propylene glycol and polyethylene glycol;
the colorant is selected from the group consisting of: one or more of lemon yellow, carmine, indigo and curcumin.
6. The oral solid preparation containing the lamiditan hemisuccinate according to claim 5, wherein,
the disintegrating agent is selected from croscarmellose sodium;
the binder is selected from pregelatinized starch;
the cosolvent is selected from sodium dodecyl sulfate;
the flavoring agent is selected from steviosin and/or peppermint essence;
the preservative is selected from methylparaben;
the lubricant is selected from soybean oil;
the wetting agent is selected from glycerol;
the colorant is selected from indigo.
7. A process for the preparation of an oral solid preparation comprising lamidian hemisuccinate according to any one of claims 1-5, comprising the steps of:
(a) The lasmiditant hemisuccinate is subjected to airflow micronization treatment, and the particle size range is controlled to be D 90 Not more than 20 μm;
(b) Mixing the treated lasmiditant hemisuccinate with a filler in a hopper mixer, and sieving after fully mixing;
(c) Adding disintegrating agent, adhesive, cosolvent, correctant and colorant into the obtained Lasmid-filler mixed powder, and mixing in hopper mixer to obtain powder component of 3D printing semisolid material;
(d) Dissolving a required amount of preservative in a solvent, and then adding a required amount of wetting agent into the solvent to uniformly mix the components to prepare a liquid component of the 3D printing semisolid material;
(e) The oil phase component of the 3D printing semisolid material is a lubricant;
(g) Adding the required amount of powder components into the liquid components, uniformly mixing the powder components, adding the oil phase components into the liquid components, and uniformly mixing the oil phase components to prepare the 3D printing semisolid material;
(h) Filling the semisolid material, and sealing and preserving an aluminum bag;
(i) Filling semisolid materials containing the medicinal active ingredients into a 3D printer, and preserving heat;
(j) The semisolid material in the injector is extruded downwards by controlling a printer charging barrel screw through 3D printing software, and after extrusion, the semisolid material is deposited on a 3D printing platform;
(k) The printer controls a printing path according to the generated g code, extrudes semisolid materials layer by layer, and forms corresponding patterns on a 3D printing platform;
(l) And (5) after drying, packaging.
CN202111559311.8A 2021-12-20 2021-12-20 Oral solid preparation containing lasmidbody hemisuccinate and 3D printing preparation technology thereof Pending CN116270505A (en)

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