CN113116852A

CN113116852A - Nicergoline orally disintegrating tablet

Info

Publication number: CN113116852A
Application number: CN202110370747.6A
Authority: CN
Inventors: 范敏华; 朱逸凡
Original assignee: Zhejiang Poly Pharmaceutical Co ltd; Hainan Poly Pharmaceutical Co ltd
Current assignee: Zhejiang Poly Pharmaceutical Co ltd; Hainan Poly Pharmaceutical Co ltd
Priority date: 2021-04-07
Filing date: 2021-04-07
Publication date: 2021-07-16
Anticipated expiration: 2041-04-07
Also published as: CN113116852B

Abstract

The application provides a nicergoline orally disintegrating tablet which is stable and has good disintegrating effect, wherein microcrystalline cellulose and mannitol are used as filling agents, and crospovidone and dry starch which can be selected from croscarmellose sodium are used as disintegrating agents. The orally disintegrating tablet is prepared by a direct tabletting method, the process is simple, the quality uniformity is easy to control, and the prepared orally disintegrating tablet realizes good unification of stability and dissolution performance.

Description

Nicergoline orally disintegrating tablet

Technical Field

The application provides a nicergoline orally disintegrating tablet which is stable and has good disintegrating effect, wherein microcrystalline cellulose and mannitol are used as filling agents, and crospovidone and dry starch which can be selected from croscarmellose sodium are used as disintegrating agents.

Background

The application belongs to the field of medicaments and the field of nervous system disease medicaments, and particularly provides a nicergoline orally disintegrating tablet which is stable and has a good disintegrating effect.

Nicergoline (Nicergolent) is a semisynthetic ergoline derivative with α -receptor blocking and vasodilating effects of mefenoxate. Nicergoline can enhance energy metabolism of nerve cells, promote biosynthesis of brain protein, and promote conversion of neurotransmitter dopamine to increase nerve conduction, thereby realizing repair of neuron function and improving symptoms of brain function damage and brain deterioration.

Nicergoline is widely used for treating headache, cerebrovascular diseases, brain dysfunction, Alzheimer disease and other diseases at home and abroad, and the commercial dosage forms comprise enteric-coated tablets, sustained-release granules, capsules, injections and the like. Although research and report are reported at home and abroad as an orally disintegrating tablet formulation which is most convenient to use and has high bioavailability, no product is on the market so far. The main reason is that nicergoline is sensitive to high temperature and high humidity and has poor compatibility with various hygroscopic disintegrants such as sodium carboxymethyl starch, namely a certain contradiction exists between disintegration performance and drug stability of nicergoline tablets (not limited to orally disintegrating tablets), and the relationship between the nicergoline tablets and the drug stability is difficult to balance under the condition that the orally disintegrating dosage form is limited more.

Disclosure of Invention

Based on the previous research on nicergoline orally disintegrating tablets, the applicant tries to use a new combination of a filler and a disintegrant to construct a nicergoline orally disintegrating tablet with simple component and preparation process and low cost, and finds that the combination of the disintegrant of crospovidone and croscarmellose sodium can provide good disintegration and good stability balance, and the disintegration can be further improved by further adding dry starch.

In one aspect, the application provides an orally disintegrating tablet of nicergoline, comprising 3-10g of nicergoline, 40-80g of filler and 2-5g of disintegrant per 1000 tablets, wherein the disintegrant is selected from crospovidone, croscarmellose sodium and dry starch.

Furthermore, the nicergoline orally disintegrating tablet also comprises 2-4g of effervescent agent and 0.1-1g of lubricant per 1000 tablets; preferably, the effervescent agent is 2g of citric acid, 1.5g of sodium bicarbonate and the lubricant is 0.3g of magnesium stearate.

Further, the filler is 15g of microcrystalline cellulose and 35g of mannitol.

Further, the disintegrant is crospovidone and croscarmellose sodium.

Further, the disintegrant is crospovidone 2g and croscarmellose sodium 2 g.

Further, the disintegrant is crospovidone, croscarmellose sodium and dry starch.

Further, the disintegrating agent comprises 2g of crospovidone, 2g of croscarmellose sodium and 0.5g of dry starch

Further, the nicergoline orally disintegrating tablet is prepared by a direct compression method.

In another aspect, the application provides the use of crospovidone, croscarmellose sodium and dry starch as disintegrants in the preparation of an orally disintegrating tablet of nicergoline.

Further, the weight ratio of croscarmellose sodium to dry starch is 4: 4: 1.

the nicergoline can be purchased in the market or prepared by the user, and various auxiliary materials can be selected from products of various manufacturers according with relevant standards.

The orally disintegrating tablet is prepared by a direct tabletting method, the process is simple, the quality uniformity is easy to control, and the prepared orally disintegrating tablet realizes good unification of stability and dissolution performance and has potential of practical marketing.

Drawings

FIG. 1: dissolution results for 6 formulations are shown schematically.

Detailed Description

Main reagents and instruments:

rotary tablet presses (fly, XYP-9B);

tablet hardometer (BIOBASE, YD-2);

drug dissolution apparatus (Chuangxing, RC12 DF);

disintegration apparatus (Chuangxing, BJ-3);

liquid chromatography (shimadzu, LC 2030);

nicergoline raw material medicine: the applicant self-manufactures and meets related standards (identification and structure in melting point, thermal analysis, element analysis, spectrum and mass spectrum methods, and considers the quality in aspects of appearance, solubility, absorption, optical rotation, impurities, drying weight loss and the like);

and (3) standard substance: check in purchases

Microcrystalline cellulose: xian jin-sourced Biotechnology Ltd;

mannitol: shijiazhuang Huaxing pharmaceutical factory;

crospovidone: basf;

citric acid: shijiazhuang Huaxing pharmaceutical factory;

sodium bicarbonate: shijiazhuang Huaxing pharmaceutical factory;

lactose (amorphous): shanxi brocade medicinal adjuvant Co., Ltd;

dry starch: shanxi brocade medicinal adjuvant Co., Ltd;

croscarmellose sodium: shijiazhuang Huaxing pharmaceutical factory;

chromatographic grade acetonitrile: DIKMA

Other unexhausted reagents are of the domestic conventional variety.

EXAMPLE 1 part of the formulation List

The listed formulas are only part of representative formulas, and a large number of other formulas involved in the screening process are not shown one by one due to space, representativeness and the like.

The following formulation is a 9mm tablet by direct compression, with a hardness of 4kg, based on 1000 tablets:

formula 1:

5g of nicergoline, 15g of microcrystalline cellulose, 35g of mannitol, 3g of crospovidone, 2g of citric acid, 1.5g of sodium bicarbonate and 0.5g of magnesium stearate;

and (2) formula:

5g of nicergoline, 10g of microcrystalline cellulose, 10g of non-crystalline lactose, 30g of mannitol, 3g of crospovidone, 2g of citric acid, 1.5g of sodium bicarbonate and 0.3g of magnesium stearate;

and (3) formula:

5g of nicergoline, 20g of microcrystalline cellulose, 30g of mannitol, 2g of crospovidone, 2g of croscarmellose sodium, 2g of citric acid, 1.5g of sodium bicarbonate and 0.5g of magnesium stearate;

and (4) formula:

5g of nicergoline, 20g of microcrystalline cellulose, 30g of mannitol, 2g of crospovidone, 2g of croscarmellose sodium, 0.5g of dry starch, 2g of citric acid, 1.5g of sodium bicarbonate and 0.5g of magnesium stearate;

and (5) formula:

5g of nicergoline, 20g of microcrystalline cellulose, 30g of mannitol, 2g of crospovidone, 2g of croscarmellose sodium, 1g of dry starch, 2g of citric acid, 1.5g of sodium bicarbonate and 0.3g of magnesium stearate;

and (6) formula:

5g of nicergoline, 20g of microcrystalline cellulose, 30g of mannitol, 2.5g of croscarmellose sodium, 1.5g of dry starch, 2g of citric acid, 1.5g of sodium bicarbonate and 0.3g of magnesium stearate.

Example 2 disintegration and stability testing

And (3) testing the disintegration property:

5 pieces of the detection tablet are placed in a hanging basket of the disintegration tester, and the disintegration tester is started to record the average disintegration time. The results are as follows:

according to the detection result of the disintegration tester, the 6 formulas can basically meet the requirements; in the test of volunteer reagent buccal administration, the disintegration time recorded by volunteers is generally prolonged by about 1.5-2 times, and according to experience, the formula 1-4 can meet the actual use requirement by matching with a proper flavoring agent.

And (3) stability detection:

the tablets were taken in multiple tablets, without packaging, protected from light in a constant temperature (25 ℃) and humidity (40%) environment, and the impurity contents were recorded on

days

0, 3, 7 and 14 (since the formulations were large, the curves were difficult to distinguish in one graph, and the representative results on day 7 are shown in the table below).

Tablet 1 (i.e. nicergoline 5mg) powder was dissolved in 25mL acetonitrile with ultrasonic assistance. The initial state of the tablet solution was used as a control, the chromatographic parameters were adjusted, and the impurity peak and main peak areas were recorded.

Formulation of	Maximum single impurity (%)	Total impurities (%)
			Formulation 1	0.91±0.07	2.06±0.13
Formulation 2	1.05±0.15	1.37±0.17
			Formulation 3	0.82±0.07	1.22±0.22
Formulation 4	0.22±0.04	0.38±0.08
			Formulation 5	0.24±0.08	0.56±0.01
Formulation 6	0.77±0.06	0.99±0.11

After 14 days, the appearance of each tablet is not obviously changed, and the hardness is slightly reduced. In the aspect of impurities, the effects of the formulas 1-3 and 6 are not ideal and are close to or exceed the standard limit of 1% or 2%, and according to experience and subsequent packaging experiments, the stability cannot meet the preservation requirement of more than 1 year by adopting a conventional packaging form with lower price. The combination of crospovidone, croscarmellose sodium, and dry starch may provide suitable preservation properties.

Example 3 dissolution Performance testing

Dissolution test:

adopting a paddle method, taking 500mL of 0.1M HCl as a dissolution medium, and carrying out the steps at 100r/min and 37 ℃; 10mL of the solution was tested at 2, 4, 6, 10, 15, 20, 30 minutes and supplemented with an equal amount of fresh medium. The standard substance is prepared into a standard solution of 20 ug/mL. The two solutions were removed and the absorbance at 288nm was measured by spectrophotometry, and the elution amount and the cumulative elution rate were calculated (see the 2010 pharmacopoeia).

The results of the dissolution results of the 6 formulations are shown in fig. 1, and show that the dissolution effects of the formulations other than formulation 6 are similar, and 90% is obtained in 10 minutes, and that formulation 2 using lactose for dissolution is slightly better, and

formulations

5 and 6 having poor disintegration properties are slightly worse.

Claims

1. The nicergoline orally disintegrating tablet is characterized in that each 1000 tablets contain nicergoline 3-10g, a filling agent 40-80g and a disintegrating agent 2-5g, wherein the disintegrating agent is selected from crospovidone, croscarmellose sodium and dry starch.

2. The nicergoline orally disintegrating tablet of claim 1, further comprising 2-4g of effervescent agent and 0.1-1g of lubricant per 1000 tablets; preferably, the effervescent agent is 2g of citric acid, 1.5g of sodium bicarbonate and the lubricant is 0.3g of magnesium stearate.

3. The nicergoline orally disintegrating tablet of claim 1 or 2, wherein the filler is microcrystalline cellulose 15g and mannitol 35 g.

4. The nicergoline orally disintegrating tablet of any one of claims 1-3, wherein the disintegrant is crospovidone and croscarmellose sodium.

5. The nicergoline orally disintegrating tablet of claim 4, wherein the disintegrant is crospovidone 2g and croscarmellose sodium 2 g.

6. The nicergoline orally disintegrating tablet of any one of claims 1-3, wherein the disintegrant is crospovidone, croscarmellose sodium and dry starch.

7. The nicergoline orally disintegrating tablet of claim 6, wherein the disintegrant is crospovidone 2g, croscarmellose sodium 2g, and dry starch 0.5 g.

8. The nicergoline orally disintegrating tablet of any one of claims 1-7, prepared using a direct compression method.

9. Application of crospovidone, croscarmellose sodium and dry starch as disintegrant in preparing nicergoline orally disintegrating tablet is provided.

10. The use according to claim 9, wherein the weight ratio of crospovidone, croscarmellose sodium and dry starch is 4: 4: 1.