CN108078936B - Trimebutine maleate dispersible tablet and preparation method thereof - Google Patents
Trimebutine maleate dispersible tablet and preparation method thereof Download PDFInfo
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- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
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- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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Abstract
The invention relates to a trimebutine maleate dispersible tablet and a preparation method thereof, belonging to the technical field of medical preparations characterized by non-effective components. The tablet is composed of trimebutine maleate, auxiliary materials and auxiliary agents for adjusting the integral uniformity and dispersibility of the tablet, wherein the auxiliary materials and the auxiliary agents are added by taking trimebutine maleate as a reference, and the auxiliary materials are composed of lactose, starch and hydroxypropyl methylcellulose E5. The application is applied to the processing of gastrointestinal dysfunction preparations, and has the advantages of stable release performance, high bioavailability and the like under different in vitro environments.
Description
Technical Field
The invention relates to a trimebutine maleate dispersible tablet and a preparation method thereof, belonging to the technical field of medical preparations characterized by non-effective components.
Background
Trimebutine maleate is a pioneer research of the company pfeiri and is now on the market in various places throughout the world. It is a noncompetitive antispasmodic medicine, has obvious effect of resisting 5-hydroxytryptamine, does not influence normal movement of stomach and intestine, and can bidirectionally regulate abnormal movement. The traditional Chinese medicine composition is suitable for improving symptoms such as inappetence, nausea, vomit, belching, abdominal distension, borborborygmus, abdominal pain, diarrhea, constipation and the like caused by gastrointestinal motility dysfunction caused by gastrointestinal dysfunction, and has good curative effect on irritable bowel syndrome.
The chemical name of trimebutine maleate is 3,4, 5-trimethoxybenzoic acid (2-dimethylamino-2-phenyl) butyl ester maleate, and the molecular formula is C22H29NO5.C4H4O4Molecular weight of 503.54, and its structural formula is:
the trimebutine maleate can be prepared into tablets, capsules and dry suspensions. Although these techniques are relatively mature, they still have a number of disadvantages. After the oral solid preparation enters the body, the oral solid preparation can be absorbed by the organism through a biological membrane after being dissolved out. However, the existing trimebutine maleate has slow dissolution rate and slow effect. Therefore, the development of the trimebutine maleate dispersion preparation with higher release speed, high bioavailability and simple production process is very practical.
CN1507861A, a chinese patent, discloses a trimebutine maleate tablet and its preparation method. The tablet prepared by the patent technology has simple formula and low production cost, but is incompletely released in different in-vitro environments, and has lower bioavailability.
CN1927185A, a chinese patent, discloses a trimebutine maleate sustained release tablet with a quick release part and a preparation process thereof, the preparation process comprises a double-layer tablet and a sustained release tablet prepared by distributed granulation and mixed tabletting, the process is complex, and the cost is high.
CN1839816A, a chinese patent, discloses a dispersible tablet of trimebutine maleate and its preparation method. The trimebutine maleate tablet prepared by the patent technology is bitter in taste, the bitter taste of the trimebutine maleate can be completely covered by compounding a flavoring agent and a sweetening agent, but the trimebutine maleate is easy to degrade, and the trimebutine maleate dispersible tablet prepared by the method has low stability.
The present application was made based on this.
Disclosure of Invention
The technical defects are that the application firstly provides a trimebutine maleate dispersion tablet with rapid dissolution and stable quality.
In order to achieve the purpose, the technical scheme adopted by the application is as follows:
the trimebutine maleate dispersible tablet consists of trimebutine maleate, auxiliary materials and auxiliary agents for adjusting the integral uniformity and the dispersibility of the tablet, wherein the auxiliary materials and the auxiliary agents are added by taking trimebutine maleate as a reference, the auxiliary materials consist of lactose, starch and hydroxypropyl methylcellulose E5, and each 100g of trimebutine maleate is added with the following components in percentage by mass:
50-70 parts of lactose is added into the milk,
10-30 parts of pregelatinized starch,
15-20 parts of tartaric acid, wherein,
hydroxypropyl methylcellulose E56-18 (a) is added,
1-30 of auxiliary agent.
Further, as preferable:
the lactose is lactose monohydrate.
The auxiliary agent comprises a lubricant, a disintegrating agent and a flow aid, wherein the addition mass ratio of the disintegrating agent to the lubricant to the flow aid to the trimebutine maleate is as follows: disintegrating agent: 10-20, lubricant: 1-3, glidant: 2-5, and the arrangement of the auxiliary agent is used for adjusting the overall uniformity and dispersibility of the tablet.
More preferably:
the lubricant is selected from one or more of glyceryl behenate, glyceryl monostearate, stearic acid, magnesium stearate and glyceryl palmitostearate, and is preferably magnesium stearate.
The disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose, microcrystalline cellulose, crospovidone and sodium carboxymethyl starch, and is preferably sodium carboxymethyl starch.
The glidant is any one or more of talcum powder and colloidal silicon dioxide, and preferably the colloidal silicon dioxide. The glidant can reduce the friction between granules and between tablets and the wall of a die hole and endow the tablets with smooth and beautiful surface, when one or a mixture of talcum powder and colloidal silicon dioxide is selected as the glidant, particularly colloidal silicon dioxide is selected as the glidant, the fluidity of the granules can be improved, the tablets have smooth and beautiful surface effects, when the water absorption capacity reaches 40 percent of the self weight, the tablets can still keep the powder state, can still effectively thicken in nonpolar and low-polar media, and improve the stability of the medicinal active ingredients wrapped in the tablets.
Meanwhile, the application also provides a preparation method of the trimebutine maleate dispersible tablet with the characteristics, the trimebutine maleate dispersible tablet is used as a raw material, lactose, starch and hydroxypropyl methylcellulose E5 are used as auxiliary materials, and auxiliary agents are added to prepare the trimebutine maleate dispersible tablet, wherein the auxiliary materials comprise the following steps:
1) weighing raw and auxiliary materials according to the prescription amount, and sieving the auxiliary materials. The number of the sieved meshes is not more than 80 meshes;
2) weighing purified water according to the prescription amount, adding hydroxypropyl cellulose E5 according to the prescription amount, stirring and dissolving to prepare a bonding agent with the concentration of 1-15%;
3) sequentially adding trimebutine maleate, lactose, pregelatinized starch and tartaric acid into a wet granulator for premixing, and then adding a binder for wet granulation;
4) drying in oven, sieving, grading (the sieve mesh number is no more than 18 meshes), and adding adjuvant for total mixing;
5) and (6) tabletting.
Further, as preferable:
in the step (2), the concentration of the adhesive is 5-10%. In the production process, the inventor finds that when the concentration of the binder is too low (below 5%), the tablet has poor forming effect and is easy to generate loose particles due to weak binding action among the components, the loose particles also cause more contact between the tablet and air, and the active ingredients are easy to generate oxidation action to cause deterioration, so that the drug property stability of the tablet is poor; with the increase of the concentration of the binding agent, when the concentration of the binding agent is controlled to be 5-10%, the components have good dispersibility and cohesiveness, and subsequent granulation, drying, granule finishing and tabletting are carried out on the basis to obtain tablets with stable drug properties; when the concentration of the binder exceeds 10%, a severe sticking phenomenon occurs, which seriously affects the production.
During this concentration phase we performed several experiments and during the experiments we found unexpectedly: when the concentration of the adhesive is 5%, the surface activity of the hypromellose aqueous solution can be fully exerted, so that the tablet has very good dispersibility and cohesiveness, and the storage stability of the tablet is optimal.
Therefore, compared with the prior art, the trimebutine maleate dispersible tablets provided by the application have the following advantages and remarkable progresses:
(1) the medicine is dissolved out quickly and has stable quality. The trimebutine maleate prepared by the application mainly comprises three parts, namely raw materials, auxiliary materials and auxiliary agents, wherein the raw materials exist as active pharmaceutical ingredients, in the auxiliary materials, hydroxypropyl methylcellulose E5 is mixed with water and then used as an adhesive to be mixed with the raw materials and other components, and the active pharmaceutical ingredients are matched with lactose (preferably lactose monohydrate) and pregelatinized starch to endow the tablet inner core with good physical stability and drug property stability; then the granules formed by the raw materials and the auxiliary materials are mixed with the auxiliary agent and tabletted, and the tablet is matched with the inner core while keeping the smoothness and hardness of the tablet, so that the good dissolution of the tablet is ensured.
(2) The preparation method is simple, coating is not needed, the process is simple, and the cost is reduced; does not need complex preparation equipment and is easy for industrialized mass production. In the preparation process of the tablet, the related equipment is only a wet granulator and a tablet press, so that complex on-machine equipment is not needed, the process has strong universality, and the industrial development production is facilitated.
Detailed Description
This embodiment is further described below with reference to examples, but the present invention is only illustrated by the most preferred embodiments, and the present application is not limited thereto.
In the following examples, trimebutine maleate was obtained from the east asia pharmaceutical industries, ltd, zhejiang; lactose monohydrate purchased from DFE Pharma; pregelatinized starch was purchased from Shanghai Carlekang coating technology, Inc.; tartaric acid purchased from dr.mao; sodium carboxymethyl starch purchased from DFE Pharma; hypromellose carrekang, type E5; purified water was prepared from Zhejiang Angerican pharmaceuticals, Inc.; magnesium stearate is purchased from Anhui mountain river pharmaceutic adjuvant, Inc.; colloidal silica is available from Anhui mountain river pharmaceutic adjuvant, Inc.
And (3) wet granulating machine: fuji Yao electromechanical science and technology development (Shanghai) Inc., model 2L-FHSG 20; the tablet press is ZP14, a product of Beijing national medicine Longli technology GmbH.
Example 1
The preparation method comprises the following steps:
1) weighing raw materials and auxiliary materials according to the prescription amount, and sieving the auxiliary materials with a 80-mesh sieve;
2) weighing purified water according to the prescription amount, adding hydroxypropyl cellulose according to the prescription amount, stirring and dissolving to prepare a binding agent with the concentration of 5%;
3) sequentially adding trimebutine maleate, lactose monohydrate, pregelatinized starch and tartaric acid into a wet granulator for premixing, and then adding a binder for wet granulation;
4) drying in an oven, sieving with a 18-mesh sieve, grading, and adding the auxiliary agent for total mixing;
5) and (6) tabletting.
Example 2
The preparation method comprises the following steps:
1) weighing raw and auxiliary materials according to the prescription amount, and sieving the auxiliary materials with a 80-mesh sieve;
2) weighing purified water according to the prescription amount, adding hydroxypropyl cellulose according to the prescription amount, stirring and dissolving to prepare a binding agent with the concentration of 5%;
3) sequentially adding trimebutine maleate, lactose monohydrate, pregelatinized starch and tartaric acid into a wet granulator for premixing, and then adding a binder for wet granulation;
4) drying in an oven, sieving with a 18-mesh sieve, grading, and adding the auxiliary agent for total mixing;
5) and (6) tabletting.
Example 3
The preparation method comprises the following steps:
1) weighing raw and auxiliary materials according to the prescription amount, and sieving the auxiliary materials with a 80-mesh sieve;
2) weighing purified water according to the prescription amount, adding hydroxypropyl cellulose according to the prescription amount, stirring and dissolving to prepare a binding agent with the concentration of 5%;
3) sequentially adding trimebutine maleate, lactose monohydrate, pregelatinized starch and tartaric acid into a wet granulator for premixing, and then adding a binder for wet granulation;
4) drying in an oven, sieving with a 18-mesh sieve, grading, and adding the auxiliary agent for total mixing;
5) and (6) tabletting.
Comparative example 1
The patent with application number 201510616218.4 is the preparation of a sustained release preparation of trimebutine maleate.
The components are weighed according to the following amounts:
the EC alcohol solution accounts for 3 percent of the total weight of trimebutine maleate particles,
7.5g of magnesium stearate,
colloidal silica 5 g.
The preparation method comprises the following steps:
1) respectively crushing trimebutine maleate, butylated hydroxyanisole, hexadecanol, attapulgite, lactose and fumaric acid, and sieving with a 100-mesh sieve to obtain fine powder for later use; weighing according to the prescription amount, and premixing;
2) placing the mixed materials in a wet granulator, adding the EC alcohol solution with the prescription amount, mixing and granulating;
3) drying wet granules in a fluidized bed to obtain dry granules, and sieving and grading;
4) adding magnesium stearate and colloidal silicon dioxide in the prescribed amount into the dry granules, and mixing to obtain granules before tabletting;
5) and (6) tabletting.
The results of the dispersion uniformity and dissolution test are as follows:
according to the second part of the Chinese pharmacopoeia 2015 edition, the dissolution and the dispersion uniformity of the samples in examples 1 to 3 are detected, and the dissolution is detected in comparative example 1.
TABLE 1 Dispersion homogeneity of examples 1 to 3
| Numbering | Hardness (N) | Dispersion uniformity (min) | Dispersibility |
| Example 1 | 36.3 | 1.8 | Good effect |
| Example 2 | 37.5 | 2.0 | Good effect |
| Example 3 | 38.1 | 2.0 | Good effect |
TABLE 2 dissolution rates of examples 1 to 3
| Time (h) | 15min | 30min |
| Example 1 | 91.8％ | 98.6％ |
| Example 2 | 92.5％ | 97.4％ |
| Example 3 | 91.4％ | 95.6％ |
Table 3 dissolution of comparative example 1
| Time (h) | 2 | 4 | 6 | 8 | 10 | 12 |
| Comparative example 1 | 20.1％ | 25.4％ | 43.4％ | 57.4％ | 69.5％ | 77.1％ |
As can be seen from the comparison of tables 1 to 3, the dissolution rate of comparative example 1 in 12 hours is still less than 80%, and the dissolution rate and the absorption rate are slow. The comparative example is a sustained-release tablet which mainly plays the roles of delaying and even controlling the release of sustained-release components in the medicine in vivo and maintaining the medicine content in the blood of a medicine receiver, thereby achieving the purpose of prolonging the medicine effect.
The trimebutine maleate preparation prepared by the formula can be completely disintegrated within about 2min when dissolved in water, the dissolution rate within 15 min can reach more than 90%, and the dissolution rate within 30 min can reach about 98%, so that high bioavailability is realized. The dispersible tablet can be quickly disintegrated to form uniform viscous suspension when meeting water. The medicine is convenient to take and quick to absorb,
achieving the purpose of quick effect.
Influence of the Binder concentration
In the application, the hydroxypropyl cellulose is dissolved in water to prepare a binding agent, and the binding agent plays a very crucial role in influencing the forming and stabilizing performance of the tablet.
The concentration (mass concentration) of the binder was tested based on example 3, and specifically analyzed as follows:
TABLE 4 stability of tablets at different binder concentrations
In the production process, the inventor finds that when the concentration of the binder is too low (below 1%), the tablet has poor forming effect and is easy to generate loose particles due to weak binding action among the components, the loose particles also cause more contact between the tablet and air, and the active ingredients are easy to generate oxidation action to cause deterioration, so that the drug property stability of the tablet is poor; with the increase of the concentration of the binding agent, when the concentration of the binding agent is controlled to be 5-10%, the components have good dispersibility and cohesiveness, and on the basis, subsequent granulation, drying, granule finishing and tabletting are carried out, so that the tablets with stable drug properties can be obtained.
During this concentration phase we performed several experiments and during the experiments we found unexpectedly: when the concentration of the adhesive is 5%, the surface activity of the hypromellose aqueous solution can be fully exerted, so that the tablet has very good dispersibility and cohesiveness, and the storage stability of the tablet is optimal.
Dissolution test
The dissolution rates of sample 1 (example 1), sample 2 (example 2), sample 3 (example 3) and a control (pfeiffer france) were measured in media of ph1.2, ph4.0 and ph6.8, respectively, and the results are shown below.
TABLE 5 dissolution rate of pH1.2 medium
| Time (min) | Sample 1 | Sample 2 | Sample 3 | Reference substance |
| 15 | 91.8％ | 92.5％ | 90.8％ | 91.4％ |
| 30 | 98.6％ | 97.4％ | 95.6％ | 95.6％ |
| 45 | 98.8％ | 97.9％ | 97.3％ | 98.1％ |
TABLE 6 dissolution rate of pH4.0 medium
| Time (min) | Sample 1 | Sample 2 | Sample 3 | Reference substance |
| 15 | 41.6％ | 42.9％ | 44.7％ | 44.2％ |
| 30 | 43.6％ | 44.2％ | 45.8％ | 45.5％ |
| 45 | 45.9％ | 46.3％ | 47.7％ | 47.1％ |
TABLE 7 dissolution rate comparison table of pH6.8 medium
| Time (min) | Sample 1 | Sample 2 | Sample 3 | Reference substance |
| 15 | 18.8％ | 20.3％ | 19.2％ | 19.3％ |
| 30 | 20.4％ | 22.6％ | 20.1％ | 21.6％ |
| 45 | 22.8％ | 24.7％ | 23.2％ | 24.0％ |
As can be seen from the comparison of the above tables 5-7, the dissolution rates of the trimebutine maleate preparation of the invention and the preparation of French primula are both over 85 percent in the medium with pH of 1.2; the dissolution characteristics of the trimebutine maleate preparation of the invention in three mediums of pH1.2, pH4.0 and pH6.8 are basically consistent with the dissolution characteristics of the original preparation, which shows that the trimebutine maleate dispersible tablet of the invention has stable effect in different environments, is not inferior to the original research, and realizes higher bioavailability.
Stability test
Test samples: sample 1 (example 1), sample 2 (example 2), sample 3 (example 3), control (pfeiffer, france).
The test method comprises the following steps: respectively standing for six months under the accelerated stability test condition, measuring the content change by taking trimebutine maleate and related substances as indexes, and respectively sampling and detecting in 0 th, 1 st, 3 th and 6 th months, specifically referring to table 8.
TABLE 8 stability parameter comparison Table under different implementation conditions
As can be seen from Table 8, after standing for 6 months, the content of the related substances in the control was 0.66%, and the content was reduced to 0.71%; the contents of related substances in the embodiment 1 and the embodiment 2 are respectively 0.41%, 0.45% and 0.49%, the content reduction rate is below 0.5%, and the storage stability of the product is better.
The above description is provided for the purpose of describing the preferred embodiments of the present invention in more detail, and it should not be construed that the embodiments of the present invention are limited to the description above, and it will be apparent to those skilled in the art that the present invention can be implemented in many different forms without departing from the spirit and scope of the present invention.
Claims (6)
1. The trimebutine maleate dispersible tablet is characterized by comprising trimebutine maleate, auxiliary materials and auxiliary agents for adjusting the integral uniformity and the dispersibility of the tablet, wherein the auxiliary materials and the auxiliary agents are added by taking trimebutine maleate as a reference, the auxiliary materials comprise lactose, pregelatinized starch, hydroxypropyl methylcellulose E5 and tartaric acid, the auxiliary agents comprise lubricants, disintegrants and glidants, and each 100g of trimebutine maleate is added with the following components by mass:
lactose (50-70) g, lactose,
pregelatinized starch (10-30) g,
15-20 g of tartaric acid (total weight of tartaric acid),
hydroxypropyl methylcellulose E5 (6-18) g,
10-20 g of disintegrating agent(s),
lubricant (1-3) g, lubricant (1-3),
glidant (2-5) g;
the disintegrating agent is sodium carboxymethyl starch; the glidant is colloidal silicon dioxide.
2. The dispersible tablet of trimebutine maleate, according to claim 1, wherein: the lactose is lactose monohydrate.
3. The dispersible tablet of trimebutine maleate, according to claim 1, wherein: the lubricant is selected from any one or more of glyceryl behenate, glyceryl monostearate, stearic acid, magnesium stearate and glyceryl palmitostearate.
4. A method for preparing trimebutine maleate dispersible tablets according to any one of claims 1 to 3, wherein trimebutine maleate is taken as raw material, lactose, pregelatinized starch, hypromellose E5 and tartaric acid are taken as auxiliary materials, and auxiliary agents are added for preparation according to the following steps:
1) weighing raw and auxiliary materials according to the prescription amount, and sieving the auxiliary materials;
2) weighing purified water according to the prescription amount, adding hydroxypropyl cellulose E5 according to the prescription amount, stirring and dissolving to prepare a binding agent with the concentration of 5% -10%;
3) sequentially adding trimebutine maleate, lactose, pregelatinized starch and tartaric acid into a wet granulator for premixing, and then adding a binder for wet granulation;
4) drying in an oven, sieving, granulating, and adding the auxiliary agent for total mixing;
5) and (6) tabletting.
5. The process for the preparation of dispersible tablets of trimebutine maleate, as claimed in claim 4, wherein: in the step (1), the sieve is not larger than 80 meshes.
6. The process for the preparation of dispersible tablets of trimebutine maleate, as claimed in claim 4, wherein: in the step (4), sieving is carried out to ensure that the sieve does not exceed 15 meshes.
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| EP2481403A1 (en) * | 2011-02-01 | 2012-08-01 | Deva Holding Anonim Sirketi | Pharmaceutical combination of otilonium and trimebutine |
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| JPH03275622A (en) * | 1990-03-26 | 1991-12-06 | Teisan Seiyaku Kk | Oral solid preparation containing trimebutine maleate |
| CN1289077C (en) * | 2002-12-19 | 2006-12-13 | 海南普利制药有限公司 | Trimebutine maleate tablet and preparing method thereof |
| CN100393311C (en) * | 2006-01-26 | 2008-06-11 | 孙伟丰 | Trimebutine maleate dispersion tablet |
| US8343978B2 (en) * | 2008-08-04 | 2013-01-01 | Adds Pharmaceuticals Llc | Fast onset orodispersable tablets |
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| EP2481403A1 (en) * | 2011-02-01 | 2012-08-01 | Deva Holding Anonim Sirketi | Pharmaceutical combination of otilonium and trimebutine |
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| 分散片研究进展;黄大福;《临床医药文献杂志》;20171231;第4卷(第47期);第9289-9291页 * |
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Denomination of invention: Trimebutine maleate dispersible tablets and its preparation method Effective date of registration: 20230601 Granted publication date: 20191227 Pledgee: Bank of Ningbo Co.,Ltd. Shaoxing Branch Pledgor: ZHEJIANG ANGLIKANG PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980042571 |