CN109200026B

CN109200026B - Felodipine sustained-release tablet and preparation method thereof

Info

Publication number: CN109200026B
Application number: CN201710532921.6A
Authority: CN
Inventors: 张建立; 李瑞兰; 汪连弟; 陈婧; 石丽; 王立芹; 解玉红; 陈红燕; 方贤罗
Original assignee: Beijing Sihuan Kebao Pharmaceutical Co ltd
Current assignee: Beijing Sihuan Kebao Pharmaceutical Co.,Ltd.
Priority date: 2017-07-03
Filing date: 2017-07-03
Publication date: 2021-01-05
Anticipated expiration: 2037-07-03
Also published as: CN109200026A

Abstract

The invention relates to a felodipine sustained-release tablet, which comprises the following raw and auxiliary materials in percentage by weight: 1-5% of felodipine, 30-80% of framework material, 1-20% of filler, 1-10% of solubilizer, 10-30% of excipient, 1-10% of adhesive and 0.01-0.1% of antioxidant.

Description

Felodipine sustained-release tablet and preparation method thereof

Technical Field

The invention relates to felodipine sustained-release tablets and a preparation method thereof, belonging to the field of pharmacy.

Background

Felodipine (felodipine) is a third generation dihydropyridine calcium antagonist used to treat hypertension by inhibiting the influx of extracellular calcium in arteriolar smooth muscle and reducing peripheral vascular resistance.

Felodipine is a dihydropyridine calcium channel antagonist, is first marketed in Denmark in 1988, is a high-efficiency, safe and well-tolerated hypertension treatment drug, is safe for the elderly or patients with coronary heart disease, heart failure, renal insufficiency, asthma, peripheral vascular disease, gout or diabetes, and is used for treating hypertension in a plurality of countries.

Scientific research finds that simple hypertension can cause damage to the viscera, but blood pressure fluctuation causes serious damage to the viscera. The felodipine common tablet needs to be taken for multiple times, which inevitably causes great change of blood concentration, thereby causing great fluctuation of blood pressure and damaging human body vital organs such as heart, kidney and the like.

Patent CN 101843598A discloses a preparation method of felodipine sustained-release tablets, which mainly adopts a part of sustained-release materials to be mixed with a filler and a main drug, and the mixture is granulated by a wet method. Drying, mixing with the rest of the delayed release material, tabletting, and coating. Generally, the particles and the powder have large particle size difference, so the requirement on equipment in the production process is high, and the particles are likely to be layered by carrying and vibrating in the production process, so that the content of the slow-release material is uneven, the release is uneven, and the risk is brought to the use of a patient.

The patent CN 102552200A discloses a felodipine sustained-release tablet and a preparation method thereof, the sustained-release tablet is mainly prepared by mixing felodipine, high-viscosity hydroxypropyl methylcellulose, low-viscosity hydroxypropyl methylcellulose, a water-soluble filler and other auxiliary materials, and the preparation method comprises the steps of adding an adhesive to granulate after mixing the felodipine, the high-viscosity hydroxypropyl methylcellulose, the low-viscosity hydroxypropyl methylcellulose and the water-soluble filler, adding a lubricant after drying, uniformly mixing, tabletting and coating. No excipient is added in the prescription of the patent, so that the tablet is easy to collapse at the later stage of the release rate measurement, the shape difference of the tablet in a medium is larger than that of the original ground tablet, the release difference between tablets is large, and the problem of too fast release at the later stage exists.

Patent CN 104997750A discloses a felodipine sustained-release tablet and a preparation method thereof, wherein the sustained-release tablet realizes dual release mainly through a plain tablet and a coating sustained-release material. Generally, in the preparation of the main pellets for controlling the release of samples by coating the sustained-release material on the solid preparation, because the uneven coating of individual tablets during the coating process or the occasional sticking of tablets during the process is possible, which may cause the burst release of the tablets in vivo and bring about great risks to patients.

Disclosure of Invention

Aiming at the defects in the prior art, the technical problem to be solved by the invention is to provide a felodipine sustained-release tablet and a preparation method thereof, the sustained-release tablet has small release difference, uniform release speed, good content uniformity and complete release, compared with the original research, the sustained-release tablet has completely consistent dissolution phenomenon in each medium, extremely high degree of fitting the release degree with the original research, good content uniformity, and the levels of related substances and impurities are equivalent to the original research preparation, and conforms to the requirement of consistency evaluation on pharmacy.

The invention aims to provide a felodipine sustained-release tablet and a preparation method thereof.

The felodipine sustained-release tablet comprises the following raw and auxiliary materials in percentage by weight: 1-5% of felodipine, 30-80% of framework material, 1-20% of filler, 1-10% of solubilizer, 10-30% of excipient, 1-10% of adhesive and 0.01-0.1% of antioxidant.

Preferably, the raw and auxiliary materials account for the total weight of the tablet core in percentage by weight: 1-5% of felodipine, 40-70% of framework material, 5-18% of filler, 1-8% of solubilizer, 13-25% of excipient, 1-8% of adhesive and 0.01-0.1% of antioxidant.

Further preferably, the raw and auxiliary materials account for the total weight of the tablet core in percentage by weight: 1-5% of felodipine, 50-65% of framework material, 8-15% of filler, 1-5% of solubilizer, 15-20% of excipient, 1-5% of adhesive and 0.01-0.1% of antioxidant.

More preferably, the raw and auxiliary materials account for the total weight of the tablet core in percentage by weight: 1-5% of felodipine, 55-62% of framework material, 9-12% of filler, 1-5% of solubilizer, 18-20% of excipient, 3-5% of adhesive and 0.01-0.1% of antioxidant.

Wherein, the auxiliary materials also comprise 1 to 5 percent of lubricant.

The framework material is selected from one or more of hydroxypropyl methylcellulose E5, E50, K100, K4M, K15M and K15 MCR; the filler is selected from one or more of lactose, microcrystalline cellulose, starch and mannitol; the solubilizer is selected from one or more of tween-80, sodium dodecyl sulfate and polyoxyethylene hydrogenated castor oil; the excipient is selected from one or more of magnesium trisilicate, diatomite and kaolin; the adhesive is selected from hydroxypropyl cellulose and/or ethyl cellulose; the antioxidant is selected from propyl gallate and/or vitamin C; the lubricant is sodium stearyl fumarate.

The invention further provides a preparation method of the felodipine sustained-release tablet, which comprises the following steps:

step a, adding felodipine serving as a raw material, an antioxidant serving as an auxiliary material and a solubilizer into an ethanol solution for dissolving to obtain a raw material solution; adding the adhesive into an ethanol solution for dissolving to obtain an adhesive solution;

b, uniformly mixing the framework material and the excipient to obtain a mixture I; uniformly mixing the fillers to obtain a mixture II;

and c, mixing the mixture I and II obtained in the step b, adding the raw material solution and the adhesive solution obtained in the step a, granulating, grading and tabletting to obtain the finished product.

Further, the mass-to-volume ratio (g/ml) of felodipine to the ethanol solution in the step a is 1: (20-30); the mass-to-volume ratio (g/ml) of felodipine to ethanol solution is preferably 1: 20.

further, the mass-to-volume ratio (g/ml) of the adhesive to the ethanol solution in the step a is 1: (10-20); preferably, the mass-to-volume ratio (g/ml) of the adhesive to the ethanol solution in the step a is 1: 15.

the invention has the beneficial effects that:

the sustained-release tablet controls the release speed by matching the sustained-release material, and the excipient and the sustained-release material are premixed, so that the release speed of the tablet is extremely uniform, the tablet is completely consistent with the dissolution phenomenon of the original preparation in each medium, the degree of release in each medium is extremely high in accordance with the original preparation, and the problems of large release difference and nonuniform release speed among tablets are solved; felodipine is sensitive to light, is easy to oxidize, is an insoluble drug and has small specification, and the problems of incomplete later release of felodipine, poor content uniformity of small-specification drugs and rapid increase of impurities in the preparation process and the stability process are solved by adding felodipine, a solubilizer and an antioxidant into an ethanol solution and carrying out wet granulation.

Detailed Description

Example 1

The preparation method comprises the following steps:

step a, adding the felodipine, antioxidant propyl gallate and solubilizer polyoxyethylene hydrogenated castor oil into 95% ethanol solution to dissolve [ felodipine: 95% ethanol 1:20(g/ml) ], to obtain a raw material solution; the binder hydroxypropylcellulose was dissolved in a 95% ethanol solution [ binder: 95% ethanol 1:15(g/ml) ], to obtain an adhesive solution;

step b, uniformly premixing sustained-release materials hydroxypropyl methylcellulose K15M and hydroxypropyl methylcellulose E50 by an equivalent progressive method, and uniformly mixing with excipient magnesium trisilicate by an equivalent progressive method to obtain a mixture I; premixing anhydrous lactose and microcrystalline cellulose uniformly according to an equivalent gradual addition method to obtain a mixture II;

c, uniformly mixing the mixture I and the mixture II in a three-dimensional mixer; b, transferring the mixture into a wet granulator after mixing, starting mixing, adding the raw material solution obtained in the step a, and shearing at a high speed for 1 min; adding the adhesive in the step a, and shearing at a high speed for 2 min; sieving with 20 mesh sieve, and grading;

d, placing the wet granules in a boiling granulation dryer for drying, wherein the moisture content of the granules is controlled to be less than 3%; sieving the dry granules with a 20-mesh sieve in a swing granulator; adding a proportional amount of sodium stearate fumarate, and manually mixing uniformly;

step e, tabletting (the hardness is 70-100N); coating (weight gain is 2-4%).

The fitting degree (F2) of the release degree of the sustained-release tablet self-made in the embodiment and the original developing agent and related substances are taken as investigation indexes, and the investigation results are shown in the following tables 1 and 2:

TABLE 1 EXAMPLE 1 Release Rate results of the extended release tablet compared to the original formulation (size 2.5mg)

TABLE 2 EXAMPLE 1 comparison of the extended release tablet formulation with the original formulation (size 2.5mg)

From the above test results, it can be seen that the sustained-release tablet prepared in example 1 has a high degree of fit with the original formulation in each medium, a uniform release rate, and an impurity level equivalent to that of the original formulation.

Note that: the determination method and limit of related substances of the product are both formulated by referring to related substances under the item of felodipine sustained-release tablets in British pharmacopoeia (2009 edition);

note two: the equivalent gradual addition method refers to that a small amount of medicine is mixed with other medicines with equal mass, and the medicines are added in an amount which is multiplied until the medicines are completely mixed.

Example 2

Raw and auxiliary materials	Prescription dose of mg	2000 tablets g
			Felodipine	5.0mg	10g
Hydroxypropyl cellulose LF	10mg	20g
			Hydroxypropyl methylcellulose E50	100mg	200g
Hydroxypropyl methylcellulose K15M	25mg	50g
			Anhydrous lactose	20mg	40g
Polyoxyethylene hydrogenated castor oil	5.0mg	10g
			Microcrystalline cellulose	3mg	6g
Propyl gallate	0.06mg	0.12g
			Magnesium trisilicate	40mg	80g
Stearic acid fumaric acid sodium salt	3.9mg	8.4g

The preparation method comprises the following steps: same as example 1

The fitting degree (F2) of the release degree of the sustained-release tablet self-made in the embodiment and the original developing agent and related substances are taken as investigation indexes, and the investigation results are shown in the following tables 3 and 4:

TABLE 3 EXAMPLE 2 Release of the extended release tablet compared to the original formulation for the results (specification 5.0mg)

TABLE 4 EXAMPLE 2 comparison of the substances of the extended release tablet with those of the original formulation (specification 5.0mg)

From the above test results, it can be seen that the sustained release tablet prepared in example 2 has a high degree of fit with the original formulation in each medium, a uniform release rate, and an impurity level equivalent to the original formulation.

Example 3

Raw and auxiliary materials	Prescription dose of mg	2000 tablets g
			Felodipine	10mg	20g
Hydroxypropyl cellulose LF	10mg	20g
			Hydroxypropyl methylcellulose E50	100mg	200g
Hydroxypropyl methylcellulose K15M	25mg	50g
			Anhydrous lactose	20mg	40g
Polyoxyethylene hydrogenated castor oil	10mg	20g
			Microcrystalline cellulose	3mg	6g
Propyl gallate	0.06mg	0.12g
			Magnesium trisilicate	40mg	80g
Stearic acid fumaric acid sodium salt	4mg	8.4g

The preparation method comprises the following steps: same as example 1

The fitting degree (F2) of the release degree of the sustained-release tablet self-made in the embodiment and the original developing agent and related substances are taken as the investigation indexes, and the investigation results are shown in the following tables 5 and 6:

TABLE 5 EXAMPLE 3 Release of extended release tablets versus the original formulation for comparison of results (size 10mg)

TABLE 6 EXAMPLE 3 comparison of the substances of the extended release tablet with those of the original formulation (size 10mg)

From the above test results, it can be seen that the sustained release tablet prepared in example 3 has a high degree of fit with the original formulation in each medium, a uniform release rate, and an impurity level equivalent to the original formulation.

Example 4

Raw and auxiliary materials	Prescription dose of mg	2000 tablets g
			Felodipine	2.5mg	5g
Hydroxypropyl cellulose LF	10mg	20g
			Hydroxypropyl methylcellulose E50	100mg	200g
Hydroxypropyl methylcellulose K15M	25mg	50g
			Anhydrous lactose	20mg	40g
Sodium dodecyl sulfate	2.5mg	5g
			Starch	3mg	6g
Propyl gallate	0.06mg	0.12g
			Magnesium trisilicate	40mg	80g
Stearic acid fumaric acid sodium salt	4.2mg	8.4g

The preparation method comprises the following steps: the same as in example 1.

Example 5

Raw and auxiliary materials	Prescription dose of mg	2000 tablets g
			Felodipine	5.0mg	10g
Hydroxypropyl cellulose LF	10mg	20g
			Hydroxypropyl methylcellulose E50	100mg	200g
Hydroxypropyl methylcellulose K15M	25mg	50g
			Anhydrous lactose	20mg	40g
Polyoxyethylene hydrogenated castor oil	5.0mg	10g
			Microcrystalline cellulose	3mg	6g
Propyl gallate	0.06mg	0.12g
			Diatomite	40mg	80g
Stearic acid fumaric acid sodium salt	3.9mg	8.4g

The preparation method comprises the following steps: the same as in example 1.

The sustained-release tablets prepared in the above examples 4 and 5 have high fitting degree with the original preparation in each medium, uniform release speed and impurity level equivalent to that of the original preparation.

EXAMPLE 6 adjuvant mixing sequence screening experiment

Taking raw and auxiliary materials according to the prescription of the embodiment 1, and respectively preparing the sustained-release tablets according to the following methods:

the method comprises the following steps:

basically, the method is the same as example 1, except that the mixing sequence of the sustained-release material, the excipient and the filler in step b is as follows: uniformly mixing hydroxypropyl methylcellulose K15M and hydroxypropyl methylcellulose E50 by an equivalent progressive method to obtain a mixture I; and uniformly mixing the anhydrous lactose, the microcrystalline cellulose and the magnesium trisilicate according to an equivalent gradual addition method to obtain a mixture II.

The second method comprises the following steps:

the method of preparation of example 1.

The fitting degree of the original preparation in a 1% Tween solution dissolution medium of hydrochloric acid with pH1.2 is used as an index for inspection, the influence of the material mixing sequence of the sustained-release tablets prepared by the two methods on the release result is inspected, and the result is shown in Table 7.

TABLE 7 Effect of different preparation methods on the Release results of sustained Release tablets

Mixing sequence	Similarity factor F2 with original research
		Method 1	45.2
Method two	86.2

According to the results, the excellent effect is achieved by premixing the magnesium trisilicate and the slow release material, the slow release tablet prepared by the method has extremely high release fitting degree with the original grinding agent in a 1% Tween solution medium of hydrochloric acid with the pH value of 1.2, and the release speed of the product is uniform. Effectively solves the problem of the slow and fast release behavior of the felodipine sustained-release tablets before and after the release rate. The sample prepared in method one, in the 1% Tween solution of hydrochloric acid with the medium pH of 1.2, has a degree of fitting with the original sample, which is not qualified.

Example 7 Binder concentration screening experiment

Hydroxypropyl cellulose is dissolved in water, so that the viscosity of materials is easily larger, and the process feasibility is influenced, therefore, absolute ethyl alcohol or 95% ethyl alcohol is firstly selected for granulation, and later-stage process parameters are searched.

5 parts of 20g hydroxypropyl cellulose LF adhesive (batch: 2000 tablet amount) are respectively added with 200ml, 300ml, 400ml, 500ml and 600ml of 95% ethanol for granulation, and the influence of different adhesive concentrations on the particle fluidity, particle size, compression ratio and the fitting degree with the original grinding release is examined. The rest of the preparation method is the same as example 1. The results are shown in Table 8.

TABLE 8 Effect of different Binder concentrations on extended Release tablets

Note: medium A was a 1% Tween solution of hydrochloric acid pH1.2, and medium B was a 1% SDS solution of phosphate buffer pH 6.5.

From the results of the examination, it was found that as the amount of ethanol used in the binder increased, the flowability and compressibility of the granules became poor, the particle size became small, and the degree of fit to the original ground release was satisfactory (F2 was more than 50), but the degree of fit was decreased. The ratio of binder to ethanol is therefore preferably (1:15)

Example 8 raw material concentration screening test

Taking 4 parts of 5.0g (batch: 2000 tablets) of felodipine as a raw material, respectively adding 50ml, 80ml, 100ml and 150ml of 95% ethanol, and examining the influence of different ethanol dosage on the content uniformity of the tablets. The rest of the preparation method is the same as example 1. The results are shown in Table 9.

TABLE 9 Effect of different ethanol dosages on tablet content uniformity

Raw materials	Amount of ethanol	Ratio of feedstock to ethanol	Content uniformity (A +2.2S)
				5.0g	50ml	1：10	19.29 (fail)
5.0g	80ml	1：13	15.8 (unqualified)
				5.0g	100ml	1：20	4.3 (qualified)
5.0g	150ml	1：30	5.4 (qualified)

The detection result shows that the content uniformity of the raw materials and the ethanol are controlled to be (1:20 and 1:30), and the ratio of the raw materials to the ethanol in the liquid medicine is preferably 1: 20.

Claims

1. The felodipine sustained-release tablet is characterized in that the sustained-release tablet comprises the following raw and auxiliary materials in percentage by weight: 1-5% of felodipine, 30-80% of framework material, 1-20% of filler, 1-10% of solubilizer, 10-30% of excipient, 1-10% of adhesive, 0.01-0.1% of antioxidant and 1-5% of lubricant; the framework material is selected from one or more of hydroxypropyl methylcellulose E5, E50, K100, K4M, K15M and K15 MCR; the filler is selected from one or more of lactose, microcrystalline cellulose, starch and mannitol; the solubilizer is selected from one or more of tween-80, sodium dodecyl sulfate and polyoxyethylene hydrogenated castor oil; the excipient is selected from one or more of magnesium trisilicate, diatomite and kaolin; the adhesive is selected from hydroxypropyl cellulose and/or ethyl cellulose; the antioxidant is selected from propyl gallate and/or vitamin C; the lubricant is sodium stearate fumarate;

the felodipine sustained-release tablet is prepared by the following method:

step a, adding felodipine, an antioxidant and a solubilizer into an ethanol solution for dissolving to obtain a raw material solution; adding the adhesive into an ethanol solution for dissolving to obtain an adhesive solution;

step c, mixing the mixture I and II in the step b, adding the raw material solution and the adhesive solution in the step a, granulating, finishing granules, adding a lubricant, and tabletting;

the mass volume ratio of the adhesive to the ethanol solution in the step a is 1: (10-20); the mass-to-volume ratio of felodipine to the ethanol solution is 1: (20-30).

2. The felodipine sustained-release tablet of claim 1, wherein the raw and auxiliary materials comprise, by weight: 1-5% of felodipine, 40-70% of framework material, 5-18% of filler, 1-8% of solubilizer, 13-25% of excipient, 1-8% of adhesive, 0.01-0.1% of antioxidant and 1-5% of lubricant.

3. The felodipine sustained-release tablet of claim 2, wherein the raw and auxiliary materials comprise, by weight: 1-5% of felodipine, 50-65% of framework material, 8-15% of filler, 1-5% of solubilizer, 15-20% of excipient, 1-5% of adhesive, 0.01-0.1% of antioxidant and 1-5% of lubricant.

4. The felodipine sustained-release tablet of claim 3, wherein the raw and auxiliary materials comprise, by weight: 1-5% of felodipine, 55-62% of framework material, 9-12% of filler, 1-5% of solubilizer, 18-20% of excipient, 3-5% of adhesive, 0.01-0.1% of antioxidant and 1-5% of lubricant.

5. A process for the preparation of felodipine sustained release tablets according to any one of claims 1 to 4, which comprises the steps of:

wherein the mass-volume ratio of felodipine to the ethanol solution in the step a is 1: (20-30); the mass-volume ratio of the adhesive to the ethanol solution is 1: (10-20).

6. The method of claim 5, wherein the mass-to-volume ratio of felodipine to ethanol solution in step a is 1: 20.

7. the method of claim 5, wherein the mass-to-volume ratio of the binder to the ethanol solution in step a is 1: 15.