CN112704670B

CN112704670B - Lorcaserin hydrochloride osmotic pump controlled release preparation and preparation method thereof

Info

Publication number: CN112704670B
Application number: CN202110021875.XA
Authority: CN
Inventors: 汪电雷; 黄鹏; 蒋成君; 王重阳; 周丽
Original assignee: Anhui University of Traditional Chinese Medicine AHUTCM
Current assignee: Anhui University of Traditional Chinese Medicine AHUTCM
Priority date: 2021-01-08
Filing date: 2021-01-08
Publication date: 2022-07-15
Anticipated expiration: 2041-01-08
Also published as: CN112704670A

Abstract

The invention relates to a lorcaserin hydrochloride osmotic pump controlled release preparation and a preparation method thereof, wherein the lorcaserin hydrochloride osmotic pump controlled release preparation is a lorcaserin hydrochloride osmotic pump controlled release tablet, and comprises a tablet core and a controlled release semipermeable coating film coated on the periphery of the tablet core. The lorcaserin hydrochloride osmotic pump controlled release preparation can be slowly and stably released in the environment of gastrointestinal tracts, is easy to take and has obvious taking effect.

Description

Lorcaserin hydrochloride osmotic pump controlled release preparation and preparation method thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a lorcaserin hydrochloride osmotic pump controlled release preparation and a preparation method thereof.

Background

According to the research of the cooperative group of obesity research of global disease burden in 2015, the following characteristics are shown: in 2015, about 1.077 hundred million obese children and about 6.037 hundred million obese adults were found to be globally obese. The obesity rates for children and adults are 5% and 12%, respectively. According to the statistics of the national committee of health, the overweight rate of adults 18 years old and older in the country is 30.1%, the obesity rate is 11.9%, the overweight rate of teenagers of children 6 to 17 years old is 9.6%, and the obesity rate is 6.4%. Obesity, a health risk which is not negligible for modern people, will greatly increase the incidence of cardiovascular and cerebrovascular diseases and tumors thereof, and therefore weight-losing medicines are receiving more and more attention. At present, with the continuous and intensive research on the weight-losing mechanism, weight-losing medicaments with different mechanisms, such as sibutramine and orlistat, are developed successively. However, the clinical use of the medicines with serious adverse reactions is limited, such as sibutramine is withdrawn from the Chinese market due to cardiovascular safety, and orlistat has an increased hepatotoxicity risk.

The us FDA approved marketing approval of belviq (lorcaserin) developed by Arena pharmaceutical company, switzerland on day 6, month 27, 2012. Belviq acts by activating the 5-hydroxytryptamine receptor in the brain, which enables the patient to decrease diet and become satiated after a small meal. FAD approved the request for the marketing of lorcaserin skeleton sustained release tablets in 2016. Lorcaserin hydrochloride is the first approved weight-reducing drug for 13 years after approval of Xeronine (orlistat) by FDA since 1999, and is used for adult human body quality index (BMI) ≧ 27mg/kg²And suffering from at least one weight-related disorder. Researches find that the lorcaserin hydrochloride skeleton type sustained-release preparation has bioequivalence with a lorcaserin hydrochloride tablet, but the dosage of the lorcaserin hydrochloride should not exceed 10mg and twice a day (b.i.d), so that physical disintersion can be caused, and the risk of sudden drug release can also exist after the lorcaserin hydrochloride skeleton type sustained-release preparation and food are taken together, which can be caused by that the release mechanism of the lorcaserin hydrochloride sustained-release tablet is damaged due to the change of the environment in the gastrointestinal tract after the food is taken, so that the potential safety risk exists for patients taking the lorcaserin skeleton type sustained-release tablet. Therefore, a need exists for a device that can be in vivoAn internal stable slow-release lorcaserin hydrochloride preparation.

Disclosure of Invention

Aiming at the problems, the invention provides a lorcaserin hydrochloride osmotic pump controlled release preparation.

The lorcaserin hydrochloride osmotic pump controlled-release preparation is a lorcaserin hydrochloride osmotic pump controlled-release tablet, and comprises a tablet core and a controlled-release semipermeable coating film coated on the periphery of the tablet core.

Further, the weight of the controlled-release semipermeable coating film is 2% -5% of that of the tablet core.

Further, the controlled-release semipermeable coating film is provided with drug release holes, and the diameter of each drug release hole is 0.6-1.0 mm.

Further, the tablet core comprises the following components in percentage by weight:

8-10% of lorcaserin hydrochloride;

40-50% of a filler;

30-40% of osmotic pressure promoter;

2-3% of a wetting agent;

2-3% of a lubricant.

Further, the filler is one or a mixture of starch, lactose, microcrystalline cellulose and compressible starch;

the osmotic pressure promoter is one or more of mannitol, potassium chloride, lactose, glucose, sucrose, mannitol, and sorbitol;

the wetting agent is polyvinylpyrrolidone ethanol solution;

the lubricant is one or more of magnesium stearate, talcum powder, superfine silica gel powder, hydrogenated vegetable oil and polyethylene glycol.

Further, the hardness of the tablet core is 6.5kg/mm²-7.5kg/mm²。

Further, the controlled-release semipermeable coating membrane comprises the following concentration components:

20-40mg/ml of coating material;

1-3mg/ml of plasticizer;

pore-forming agent 2-4 mg/mL.

Further, the semipermeable membrane coating material is one or a mixture of more selected from cellulose acetate, ethyl cellulose, acrylic resin, cellulose acetate butyrate and polyvinyl alcohol;

the plasticizer is one or a mixture of more of glycerol, propylene glycol, polyethylene glycol, diethyl phthalate, dibutyl phthalate and triglyceride;

the pore-foaming agent is one selected from PEG400, PEG2000 and PEG 4000;

the controlled-release semipermeable coating film also comprises solvent acetone.

Weighing the lorcaserin hydrochloride and auxiliary materials according to the prescription amount, respectively sieving and mixing the auxiliary materials except the wetting agent, preparing soft materials by using the wetting agent, sieving and granulating by using a 20-mesh sieve again, drying at 35-45 ℃, sieving and granulating, adding the lubricant according to the prescription amount, mixing, tabletting, and controlling the pressure to be 60-80N to obtain a tablet core;

dissolving the semipermeable membrane coating material, the plasticizer and the pore-forming agent according to the formula amount in a solvent used in the coating solution, and stirring;

the tablet core is arranged in a coating pan for spray coating, and the coating process parameters are as follows: spraying at speed of 5-6ml/min, coating pan temperature of 41-50 deg.C, coating pan rotation speed of 40-50r/min, and drying and curing coated tablet after coating;

preparing a small hole with the diameter of about 0.6-1.0mm on one side or two sides of the surface of the obtained coated tablet by using a mechanical method or laser to obtain the lorcaserin hydrochloride osmotic pump type controlled release tablet.

Further, the concentration of the ethanol solution of the polyvinylpyrrolidone is more than 70%;

the curing time was 24 hours.

The lorcaserin hydrochloride osmotic pump controlled release preparation can be slowly and stably released in the environment of gastrointestinal tracts, is easy to take and has obvious medicine effect. Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the invention. The objectives and other advantages of the invention will be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.

FIG. 1 shows a graph of the effect of different osmotically active substances on drug release;

FIG. 2 shows a graph of the effect of different amounts of mannitol on drug release;

FIG. 3 is a graph showing the effect of different amounts of cellulose acetate on drug release;

FIG. 4 shows a graph of the effect of different amounts of DBP on drug release;

FIG. 5 is a graph showing the effect of different molecular weight PEGs on drug release;

FIG. 6 is a graph showing the effect of different amounts of PEG400 on drug release;

FIG. 7 shows a graph of the effect of different membrane thicknesses on drug release;

fig. 8 shows the optimal prescribed release profile of the lorcaserin hydrochloride osmotic pump type controlled release tablet.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The osmotic pump type controlled release preparation is a preparation technology which takes osmotic pressure as drug release power and takes zero-order release power as characteristic, after being taken, water enters a tablet core from a controlled release coating (semipermeable membrane) to form high osmotic pressure in the tablet, so that the saturated aqueous solution of the drug in the tablet is released from a drug release hole on the surface of the tablet. The osmotic pressure is kept constant, namely the speed of water entering the tablet core can be kept constant, so that the water absorption and expansion rate of the high polymer material is constant, the lasting constant osmotic pressure is maintained, and the drug release rate is constant. The development of osmotic pump controlled release preparations is mainly carried out on two types of medicaments, including water-soluble medicaments and indissolvable medicaments: for most water-soluble drugs (solubility 5-30g/ml), it is relatively easy to make primary osmotic pumps (EOP). The lorcaserin hydrochloride is a water-soluble drug, is easy to dissolve in a medium and can form a certain osmotic pressure in a tablet core, and the preparation of an osmotic pump is also possible.

The invention provides a lorcaserin hydrochloride osmotic pump controlled-release preparation which is a lorcaserin hydrochloride osmotic pump controlled-release tablet and comprises a tablet core and a controlled-release semipermeable coating film coated on the periphery of the tablet core.

The weight of the controlled-release semipermeable coating film is 2-5% of the weight of the tablet core. Preferably, the weight of the controlled release semipermeable coating membrane is 3 percent of the weight of the tablet core.

The controlled-release semipermeable coating film is provided with drug release holes, and the diameter of the drug release holes is 0.6-1.0mm, preferably 0.8 mm.

The tablet core comprises the following components in percentage by weight:

8-10% of lorcaserin hydrochloride;

40-50% of a filler;

30-40% of osmotic pressure promoter;

2-3% of a wetting agent;

2-3% of a lubricant.

Wherein the filler is one or more selected from starch, lactose, microcrystalline cellulose and compressible starch, preferably microcrystalline cellulose, more preferably microcrystalline cellulose with an optimal dosage of 47%.

The osmotic pressure promoter is one or more of mannitol, potassium chloride, lactose, glucose, sucrose, mannitol and sorbitol, preferably mannitol, and the optimal dosage of mannitol is 40%.

The wetting agent is a polyvinylpyrrolidone ethanol solution, specifically, a polyvinylpyrrolidone dissolved in a 70% ethanol solution is selected, and a polyvinylpyrrolidone ethanol solution with a concentration of 2% is prepared.

The lubricant is one or more selected from magnesium stearate, talcum powder, superfine silica gel powder, hydrogenated vegetable oil and polyethylene glycol, preferably magnesium stearate, and the optimal use amount of the magnesium stearate is 2%.

The hardness of the tablet core is 6.5kg/mm²-7.5kg/mm²。

The tablet core formula is that each controlled release tablet comprises the following components in percentage by weight: mannitol, microcrystalline cellulose, polyvinylpyrrolidone, which account for about 40%, 47%, 3% of the tablet core, respectively.

The controlled-release semipermeable coating film comprises the following concentration components:

20-40mg/ml of coating material;

1-3mg/ml of plasticizer;

pore-foaming agent 2-4 mg/mL.

Wherein, the semipermeable membrane coating material is one or more selected from cellulose acetate, ethyl cellulose, acrylic resin, cellulose acetate butyrate and polyvinyl alcohol, preferably cellulose acetate. Specifically, a cellulose acetate acetone solution is prepared.

The plasticizer is one or more mixture selected from glycerol, propylene glycol, polyethylene glycol, diethyl phthalate, dibutyl phthalate and triglyceride, preferably dibutyl phthalate.

The pore-forming agent is one selected from PEG400, PEG2000 and PEG4000, preferably PEG 400.

Preferably, the cellulose acetate concentration is 3 g/ml. The PEG400 and dibutyl phthalate DBP comprise 10% and 7.5% by weight of cellulose acetate, respectively, based on the weight of the cellulose acetate.

The invention also relates to a preparation method of the lorcaserin hydrochloride osmotic pump controlled release preparation, which comprises the steps of weighing the lorcaserin hydrochloride and auxiliary materials according to the prescription amount, respectively sieving and mixing the auxiliary materials except the wetting agent, preparing a soft material by using the wetting agent, sieving and granulating the mixture by using a 20-mesh sieve, drying the dried mixture at 35-45 ℃, sieving and granulating the granules, adding the lubricant according to the prescription amount, mixing the mixture, tabletting, and controlling the pressure to be 60-80N to obtain a tablet core;

dissolving the semipermeable membrane coating material, the plasticizer and the pore-forming agent according to the formula amount in a solvent used in the coating solution, and stirring; the tablet cores are placed in a coating pan for spray coating, and the coating process parameters are as follows: spraying speed is 5-6ml/min, temperature in the coating pan is 41-50 ℃, and rotating speed of the coating pan is 40-50 r/min; drying and curing the coated tablets after coating;

The wetting agent is polyvinylpyrrolidone ethanol solution, and the concentration of the ethanol solution is about more than 75%; the solvent used by the coating liquid is acetone; the curing time was 24 hours.

Example 1

A 250mg dose of lorcaserin hydrochloride osmotic pump tablet was prepared.

Tablet core: 20mg of lorcaserin hydrochloride, 100mg of mannitol, 7.5mg of polyvinylpyrrolidone and 117.5mg of microcrystalline cellulose are sieved by a sieve of 80 meshes, weighed and mixed by an equal amount progressive method, 250mg of 70% ethanol solution is added to prepare a soft material, the soft material is granulated by a sieve of 20 meshes, dried for 6 hours at 40 ℃, and 5g of magnesium stearate is added and mixed uniformly.

Preparing a coating solution: 10g of cellulose acetate is weighed and dissolved in 500ml of acetone to prepare a cellulose acetate acetone solution, 0.75g of dibutyl phthalate DBP and 1g of PEG400 are added continuously, and the solution is stirred on a magnetic stirrer without heating until the solution is completely dissolved.

Tabletting and coating: and (4) loading the mixture into upper and lower punches, adjusting the punching pressure to be 60N, filling 250mg of tablet core particles, and pressing into tablets. Placing the tablet core in a coating pan, coating with the prepared coating solution, controlling the temperature at 45 + -5 deg.C and the rotation speed at 40r/min to coat until the weight of the coating film is increased to 3%, drying at 40 deg.C for 24h, and punching a hole at the center of the coated tablet with a laser-beam drilling machine to obtain the final product with a hole diameter of 0.8 mm.

Example 2

Screening 18mg of lorcaserin hydrochloride, 90mg of mannitol, 7mg of polyvinylpyrrolidone and 110mg of microcrystalline cellulose through a 80-mesh sieve, weighing according to the prescription amount, mixing by an equivalent progressive method, adding 200mg of 70% ethanol solution to prepare a soft material, granulating through a 20-mesh sieve, drying at 40 ℃ for 6 hours, adding 4g of magnesium stearate, and uniformly mixing.

Preparing a coating solution: weighing 8g of cellulose acetate, dissolving the cellulose acetate in 500ml of acetone to prepare a cellulose acetate acetone solution, adding 0.7g of dibutyl phthalate DBP and 0.8g of PEG400, and stirring the solution on a magnetic stirrer without heating until the solution is completely dissolved.

Tabletting and coating: loading and punching, adjusting the weight of the tablet, adjusting the punching pressure to be 75N, filling 250mg of tablet core particles, and pressing into the tablet. Placing the tablet core in a coating pan, coating with the prepared coating solution, controlling the temperature at 45 + -5 deg.C and the rotation speed at 45r/min until the weight of the coating film is increased to 3%, drying at 40 deg.C for 24h, and drilling a hole with a laser drilling machine at the center of the coated tablet, wherein the hole diameter is 0.7 mm.

Example 3

Screening 25mg of lorcaserin hydrochloride, 110mg of mannitol, 8mg of polyvinylpyrrolidone and 120mg of microcrystalline cellulose through a 80-mesh sieve, weighing according to the prescription amount, mixing by an equivalent progressive method, adding 300mg of 75% ethanol solution to prepare a soft material, granulating through a 20-mesh sieve, drying at 45 ℃ for 6 hours, adding 6g of magnesium stearate, and uniformly mixing.

Preparing a coating solution: weighing 15g of cellulose acetate, dissolving in 500ml of acetone to prepare a 3% cellulose acetate acetone solution, adding 5g of dibutyl phthalate DBP and 1.2g of PEG400, and stirring on a magnetic stirrer without heating until the solution is completely dissolved.

Tabletting and coating: loading the tablets, adjusting the weight of the tablets, adjusting the punching pressure to 80N, filling 250mg of tablet core particles and pressing into tablets. Placing the tablet core in a coating pan, coating with the prepared coating solution, controlling the temperature at 45 + -5 deg.C and the rotation speed at 50r/min until the weight of the coating film is increased to 3%, drying at 40 deg.C for 24h, and drilling a hole with a laser drilling machine at the center of the coated tablet, wherein the hole diameter is 1 mm.

Test example

1. Effect of tablet core formulation on drug Release

1.1 Effect of wetting Agents and Binders

Taking the substances in the example 1 as examples, taking the lorcaserin hydrochloride and the auxiliary materials according to the prescription amount, uniformly mixing, respectively selecting water, 95% ethanol, 3% PVP 70% ethanol solution and 3% PVP 95% ethanol solution as binding agents to prepare soft materials, sieving with a 24-mesh sieve for granulation, drying at 40-50 ℃, grading with the 24-mesh sieve, adding 2% magnesium stearate, uniformly mixing and tabletting (250 mg/tablet). The conditions during granulation and tabletting were observed and the tablet hardness was measured and the results are shown in Table.1. As can be seen from the table, the indexes are all good when 3% of PVP 70% is adopted, so that 3% of PVP 70% ethanol solution is selected as the wetting agent of the lorcaserin hydrochloride. The ease of granulation of various binders was compared by the preparation process.

TABLE 1 Effect of different wetting agents and Binders

1.2 Effect of osmotically active substances

Osmotic pressure active substances are added into the osmotic pump tablet core to adjust the osmotic pressure difference between the inside and the outside of the coat membrane. Respectively selecting equal amount of mannitol, glucose and sodium chloride as osmotic pressure active substances, preparing lorcaserin hydrochloride osmotic pump controlled release tablet according to the above preparation process without changing other components, measuring release degree at different time, and drawing release curve. The cumulative release of the drug is shown in FIG. 1, and the similarity determination is shown in Table 2.

TABLE 2 results of similarity analysis of different penetrants

"+" is similar; "-" are not similar. The results show that different kinds of penetration enhancers selected in the tablet core prescription have obvious influence on the release of the lorcaserin hydrochloride osmotic pump controlled release tablet, the release curve is evaluated by similar factors, and the similar factor f between every two tablets₂Between 32.89 and 41.95 (f)₂Less than or equal to 50). In the method, because the release curve of mannitol is relatively flat, mannitol as carbohydrate has no adverse effect on obese patients, and mannitol is comprehensively considered and selected as an osmotic pressure active substance.

1.3 Effect of the amount of osmotically active substance mannitol on Release

Mannitol is selected as an osmotic pressure active substance, and mannitol accounting for 30%, 40% and 50% of the weight of the tablet is added into a tablet core prescription respectively. Other components in the tablet core prescription are unchanged, the lorcaserin hydrochloride osmotic pump controlled release tablet is prepared according to the preparation process, the accumulative release degrees of different tablets are measured, and a curve of the accumulative release degrees to time is drawn. The cumulative release is shown in FIG. 2, and the similarity determinations are shown in Table 3.

TABLE 3 Effect of different contents of mannitol on drug Release

"+" indicates similarity and "-" indicates dissimilarity. The results show that: the osmotic pump tablet core prescription selects osmotic pressure active substance mannitol with different proportions, has no obvious influence on the release of the lorcaserin hydrochloride osmotic pump controlled release tablet, and uses a similar factor f₂Drug release profiles were evaluated. The dosage of the selected osmotic pressure active substance mannitol is not less than 30%. With the increase of the proportion of osmotically active substances, the in vitro release rate of the drug tends to increase.

2. Effect of coating solution formulation on drug Release

2.1 selection of coating solution concentration

Preparing 1%, 3% and 5% cellulose acetate acetone solutions according to the weight-volume ratio, adding equal amounts of dibutyl phthalate DBP and PEG400, coating the same batch of tablet cores prepared in the example 1, and observing the release degree of the medicament, wherein the cumulative release degree of the medicament is shown in a figure 3, and the similarity judgment is shown in a table 4.

TABLE 4 Effect of different amounts of cellulose acetate on drug Release

"+" like "-" are not similar. The results show that: cellulose acetate with different concentrations is selected as a coating material in the coating liquid formula to obviously influence the release of the lorcaserin hydrochloride osmotic pump controlled release tablet, the release curve is evaluated by similar factors, and the similar factor f between every two is₂Between 38.89 and 63.29. In practice, the concentration of the coating solution is found to be too low, and the coating solution is difficult to form a uniform coating film in the tablet core. When the solubility is too high, the solution blocks the lance tip. The release curve of the 3% cellulose acetate is relatively smooth as can be seen from the cumulative release curve, and the specific dosage is determined by the optimization result of the prescription.

2.2 Effect of plasticizer amount in coating solution on drug Release

The addition of a proper amount of plasticizer into the coating liquid can not only improve the plasticity and the molding property of the coating material, but also improve the adhesion form and the mechanical property of the coating film to the tablet core. DBP is selected as a plasticizer of the coating liquid, DBP which accounts for 5%, 10% and 15% of the weight of the cellulose acetate is added into the cellulose acetate acetone solution respectively, the tablet cores of the same batch are coated, the release degree of the drug is examined, the cumulative release degree of the drug is shown in a figure 4, and the similarity judgment is shown in a figure 5.

TABLE 5 results of similarity analysis of different DBP contents

"+" is similar; "-" are not similar. The results show that different amounts of plasticizer and salt are selected in the coating liquid formulaThe release of the lorcaserin hydrochloride osmotic pump controlled release tablet has obvious influence, the release curve is evaluated by similar factors, and f is between every two₂Between 35.27 and 49.09 (f)₂50) is selected herein in the range of 7.5% to 15% plasticizer, the specific amount being determined by the results of the optimization of the recipe.

2.3 Effect of different concentrations of PEG400 in coating solutions on drug Release

Other parameters in the coating liquid prescription are fixed, PEG400 coating liquid which is equivalent to 5%, 10% and 15% of the weight of cellulose acetate is respectively added into the cellulose acetate acetone solution, the tablet cores of the same batch are coated according to the preparation process to prepare the single-chamber controlled release tablet of the lorcaserin hydrochloride osmotic pump, the accumulative release degree of the medicine is inspected, the experimental result is shown in figure 6, and the similarity judgment is shown in the table 7.

Table 7: results of similarity analysis of different PEG400 contents

"+" is similar; "-" are not similar. The results show that different amounts of pore-forming agents are selected in the coating liquid formula, the release of the lorcaserin hydrochloride is obviously influenced, the release curve is evaluated by similar factors, and f is between every two₂Between 33.39 and 49.49 (f)₂Less than or equal to 50) the amount of the pore-forming agent is selected to be within the range of 10-15 percent, and the specific amount is determined by the optimization result of the prescription. The PEG400 content is increased, and the release speed of the lorcaserin hydrochloride osmotic pump tablet is accelerated. PEG is a long-chain high-molecular polymer, and when the PEG and CA are used as the formulation of osmotic pump coating solution at the same time, the PEG and CA can be crosslinked together in the coating process, so that the mechanical strength of the formed coating film is increased, and the coating film has good plasticity; in addition, the PEG with low molecular weight has good water solubility, so that in the release process of the lorcaserin hydrochloride osmotic pump tablet, a part of PEG can be dissolved in dissolved substances, and the increase of the number of the pores on the coating film can improve the permeability of the coating film to aqueous solution, thereby accelerating the release rate of the drug.

2.4 Effect of Membrane thickness on drug Release

Selecting an optimized osmotic pump tablet core, coating the tablet core, respectively increasing the weight of a coating film by 1%, 3% and 5% relative to the tablet core, and investigating the influence of different value-added thicknesses of different coating films on the release of the lorcaserin hydrochloride osmotic pump controlled release tablet. The results of the experiment are shown in FIG. 7, and the judgment of the similarity is shown in Table 8.

TABLE 8 results of similarity analysis for different film thicknesses

"+" is similar; "-" are not similar. The result shows that the thickness of the coating film has obvious influence on the drug release, along with the thickening of the coating film, the rate of water molecules outside the coating film entering the coating film is slowed down, the time lag phenomenon occurs during drug release, and the drug release rate is in a descending trend. The release curves were evaluated by a similar factor, with f2 between pairs between 25.03 and 41.61 (f)₂Less than or equal to 50). Based on the above results analysis, the coating film thickness control condition was selected to be 3% weight gain after coating. The release rate of the drug is slowed down by the increase of the thickness of the coating film, so the weight gain parameter of the coating film needs to be controlled.

2.5 optimization of coating recipes

The selection factors are respectively A: cellulose acetate concentration; b: the dosage of PGE 400; c: DBP dosage; d: blank.

Orthogonal test is carried out to optimize the formula of the osmotic pump controlled release tablet coating solution, the factors are shown in the table 9, and the orthogonal test results and the variance analysis are shown in the tables 10 and 11.

TABLE 9 orthogonal design factor horizon

TABLE 10 orthogonal experiments and results

TABLE 11 results of ANOVA

From the range analysis, the factors influencing the release of the lorcaserin hydrochloride osmotic pump controlled release tablet are respectively as follows: b > C > A, the optimal prescription combination is A2B2C 2. As shown in the table 2-11 analysis of variance, the dosage of PEG400 and DBP has significant influence on drug release, so that the dosage is strictly controlled in the preparation of the lorcaserin hydrochloride osmotic pump controlled release tablet. In the experiment, an optimal preparation formula and an optimal preparation process are optimized by adopting an orthogonal experiment on the basis of single-factor investigation, and the optimal combined formula (each tablet) is determined to be 20mg of lorcaserin hydrochloride, 100mg of mannitol, 117.5mg of microcrystalline cellulose, 5mg of magnesium stearate, 7.5mg of PVP, a proper amount of ethanol with the concentration of 70 percent, and a coating liquid formula: 3% of cellulose acetate, 10% of PEG 40010%, 7.5% of DBP and 3.0% of coating weight increment.

3 Effect of other factors on drug Release

3.1 prescription determination of Lorcaserin hydrochloride osmotic pump single-chamber controlled release tablet

And finally determining the optimal formula of the lorcaserin hydrochloride osmotic pump tablet by combining the single factor and the orthogonal test as follows:

by adopting the formula, a tablet core with 250 mg/tablet multiplied by 500 tablet can be prepared.

The prescription of the coating liquid is as follows:

4.2 preparation Process

The preparation process comprises the following steps: respectively sieving the lorcaserin hydrochloride and auxiliary materials (except magnesium stearate) according to the prescription amount through a 100-mesh sieve, fully and uniformly mixing, preparing a soft material by using a 70% ethanol solution, sieving through a 24-mesh sieve, granulating, drying at 40 ℃, sieving through a 24-mesh sieve, granulating, adding magnesium stearate according to the prescription amount, uniformly mixing, tabletting, and controlling the pressure at 60N to obtain the tablet core. The prescribed amount of cellulose acetate, diethyl phthalate and PEG400 were dissolved in 500mL of acetone and stirred to form a homogeneous solution. And (3) placing the tablet core into a coating pan, spraying at the speed of 5ml/min, rotating at the speed of 40r/min, coating at the temperature of 41 ℃, curing in a drying oven at the temperature of 40 ℃ for 24 hours after coating, and then performing laser drilling on one side of the coated tablet to prepare a drug release pore with the diameter of 0.8mm, thus obtaining the lorcaserin hydrochloride single-layer osmotic pump controlled release tablet.

4. In vitro release mechanism investigation

The in vitro release data of the lorcaserin hydrochloride osmotic pump tablets obtained by experimental optimization are respectively fitted by zero-order, first-order and Higuchi equations, and the results are shown in Table 12.

Table 12 equation fitting table

T(h)	1	2	4	8	12	16
							F(％)	0.817	3.414	22.583	48.895	74.991	95.699
-lg(1-F)	0.00356	0.0151	0.111	0.292	0.602	1.366
							t1/2(h)	1	1.414	2	2.828	3.464	4

Fitting the release degree and the time of the lorcaserin hydrochloride single-chamber osmotic pump controlled release tablet by adopting different kinetic equations, wherein the result is as follows:

(1) zero-order equation: and performing linear fitting on t by using F at 0-16 h, wherein F is 6.36892t-3.92342(r is 0.99663).

(2) First-order equation: and performing linear fitting on t by using-lg (1-F) within 0-16 h, wherein-lg (1-F) is 0.07796t-0.13749(r is 0.93045).

(3) Higuchi equation: and performing linear fitting on t by-lg (1-F) within 0-16 h, wherein F is 25.94722t1/2-19.31419(r is 0.94197).

The result shows that the osmotic pump tablet prepared by optimization experiment has the best correlation coefficient (r is 0.9966) fitted by a zero-order equation, which shows that the equation can better describe the in-vitro release kinetic characteristics of the single-chamber controlled release tablet of the osmotic pump of the lorcaserin hydrochloride.

The release profile of the lorcaserin hydrochloride osmotic pump in aqueous hydrochloric acid is shown in figure 8. The 16 hour cumulative release results in this example were 95.69%, and the linear fit r of the release profile from 2 to 16 hours was 0.996 (where the closer r is to 1, the more zero-order release profile is demonstrated).

According to the test examples, the release effect of the lorcaserin hydrochloride osmotic pump controlled release preparation prepared by the invention is stable, and the lorcaserin hydrochloride osmotic pump controlled release preparation can be released for a long time in an acidic environment, so that the lorcaserin hydrochloride can be stably released in vivo, and the drug effect is stable.

Although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.

Claims

1. The lorcaserin hydrochloride osmotic pump controlled-release preparation is characterized by being a lorcaserin hydrochloride osmotic pump controlled-release tablet, and comprising a tablet core and a controlled-release semipermeable coating film coated on the periphery of the tablet core; the weight of the controlled-release semipermeable coating film is 2-5% of that of the tablet core;

the tablet core comprises the following components in percentage by weight:

8-10% of lorcaserin hydrochloride;

40-50% of a filler; the filler is microcrystalline cellulose;

30-40% of osmotic pressure promoter; the osmotic pressure promoter is mannitol;

2-3% of a wetting agent; the wetting agent is polyvinylpyrrolidone ethanol solution, wherein the concentration of ethanol is 70%;

2-3% of a lubricant; the lubricant is one or more of magnesium stearate, talcum powder, superfine silica gel powder, hydrogenated vegetable oil and polyethylene glycol; the controlled-release semipermeable coating film comprises the following concentration components:

20-40mg/ml of coating material; the semipermeable membrane coating material is cellulose acetate;

the dosage of the plasticizer is 7.5-15% relative to the cellulose acetate, and the plasticizer is dibutyl phthalate;

the amount of the pore-foaming agent is 10-15% relative to the amount of the cellulose acetate, and the pore-foaming agent is PEG 400;

2. The lorcaserin hydrochloride osmotic pump controlled release preparation as claimed in claim 1, wherein the controlled release semipermeable coating film is provided with drug release holes, and the diameter of the drug release holes is 0.6-1.0 mm.

3. The lorcaserin hydrochloride osmotic pump controlled release formulation of claim 1, wherein the core hardness is 6.5kg/mm²-7.5kg/mm²。

4. A preparation method of the lorcaserin hydrochloride osmotic pump type controlled release preparation as claimed in claims 1 to 3, characterized in that the lorcaserin hydrochloride is weighed according to the prescription amount, the mannitol, the polyvinylpyrrolidone and the microcrystalline cellulose are sieved by a 80-mesh sieve and then mixed with the ethanol to prepare a soft material, the soft material is sieved by a 20-mesh sieve again for granulation, the drying is carried out at 35-45 ℃, the sieved granules are then mixed with the lubricant according to the prescription amount, and the mixture is tableted, the pressure is controlled at 60-80N, and then the tablet core is obtained;

dissolving the cellulose acetate, dibutyl phthalate and PEG400 in the acetone according to the prescription amount, and stirring; the tablet cores are placed in a coating pan for spray coating, and the coating process parameters are as follows: spraying speed is 5-6ml/min, temperature in the coating pan is 41-50 ℃, and rotating speed of the coating pan is 40-50 r/min; drying and curing the coated tablets after coating;

5. The method for preparing a lorcaserin hydrochloride osmotic pump type controlled release formulation according to claim 4, wherein the curing time is 24 hours.