Pregabalin gastric floating sustained-release tablet and preparation method thereof

Abstract

The present invention provides a pregabalin gastric floating sustained-release tablet and a preparation method thereof. The tablet comprises the following ingredients in weight percentage: 7-33% active ingredient, 50-86% skeleton material, 3-15% disintegrant, 2-10% gelling agent, and 0.25-3% lubricant; wherein the active ingredient comprises pregabalin and its pharmaceutically acceptable salt, solvate, hydrate or complex. The pregabalin gastric floating sustained-release tablet prepared by the present invention has a floating time of up to 24 hours, and the tablet skeleton remains relatively intact, and the 24-hour sustained-release rate reaches more than 97%.

Description

Technical Field

[0001] The invention relates to the technical field of sustained-release preparations, and in particular to a pregabalin gastric floating sustained-release tablet and a preparation method thereof. Background Art

[0002] Clinical studies have shown that the absorption sites of pregabalin in the human body are the small intestine and ascending colon. Beyond the hepatic flexure of the colon, the absorption is very poor, indicating that the time that pregabalin stays in the absorption window is about 6 hours or less. However, ordinary sustained-release preparations pass through the hepatic flexure of the colon after about 6 hours, and the released drugs will be wasted. Therefore, it is necessary to design a pregabalin preparation that can stay in the stomach or the front part of the intestine for a long time and can continuously and steadily release drugs.

[0003] Pregabalin immediate-release preparations need to be administered multiple times a day, which can cause significant fluctuations in the blood concentration of the drug, resulting in dose-related side effects and lower drug utilization. Developing a once-daily sustained-release preparation can not only improve patient compliance, but also reduce or avoid dose-related side effects by lowering the Cmax of the drug in the blood, and increase drug efficacy by prolonging the effective concentration of the drug in plasma.

[0004] Patent CN101330907B discloses a sustained-release pharmaceutical composition containing pregabalin, a swelling agent, and a matrix forming agent (a mixture of polyvinyl acetate and polyvinyl pyrrolidone) to be taken once daily. The composition has a larger size after swelling and stronger rigidity, and achieves the purpose of gastric retention through size exclusion. Since the patent uses a mixture of polyvinyl acetate and polyvinyl pyrrolidone, which contains up to 19% polyvinyl pyrrolidone (easily soluble in water), it has the risk of a burst release effect. Moreover, the size of the preparation after swelling is smaller than or not significantly larger than the diameter of the human pylorus (13 mm), and the pyloric opening is driven by the sphincter to contract and relax, and the pyloric size of each patient is also different. The simple size exclusion mechanism in the patent does not exclude the possibility that the preparation is discharged by the pylorus shortly after taking it. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a pregabalin gastric floating sustained-release tablet and a preparation method thereof, which solves the problems of drug sudden release and the drug being discharged by the pylorus shortly after taking the preparation in the prior art.

[0006] In one aspect, the present invention provides a pregabalin gastric floating sustained-release tablet, comprising the following ingredients in percentage by weight:

[0007]

[0008] Wherein, the active ingredients include pregabalin and pharmaceutically acceptable salts, solvates, hydrates or complexes thereof.

[0009] Preferably, the skeleton material includes one or both of hydroxypropyl methylcellulose and polyethylene oxide.

[0010] Hydroxypropyl methylcellulose is made by co-processing hydropropyl methylcellulose with no more than 1% silicon. It has better compressibility and fluidity and is mainly used as a binder and skeleton material in preparations.

[0011] Polyoxyethylene is polymerized by ethylene oxide in the presence of a suitable catalyst and is mainly used as an adhesive, tablet blocker, thickener (suspending agent) and skeleton material in preparations.

[0012] More preferably, the skeleton material comprises hypromellose and polyoxyethylene, wherein the mass ratio of hypromellose to polyoxyethylene is 5:16-64.

[0013] During the experiment, the inventors found that by combining hydroxypropyl methylcellulose and polyoxyethylene as skeleton materials, the drug skeleton can remain intact for a longer time and float for a longer time, while not affecting the drug release effect and being able to release the drug continuously and smoothly.

[0014] Preferably, the hydroxypropyl methylcellulose is selected from K15M, and the polyoxyethylene is selected from any one or more of N60K, 301, and N12K.

[0015] During the experiment, the inventors found that the model of HPMC is K15M, the weight average molecular weight is about 575,000 Daltons, and the viscosity of the 2% concentration solution is 13,500-25,200 mPa.s. It is one of the main components for controlling drug dissolution and release, and can keep the skeleton structure of the tablet in the solution and prolong the floating existence time.

[0016] At the same time, the functionality of polyoxyethylene is related to its molecular weight. Polyoxyethylene with a large molecular weight delays drug release by swelling the hydrophilic skeleton to form a skeleton structure. It is one of the main components for controlling drug dissolution and release, and can enable tablets to maintain a skeleton structure in the solution and prolong the floating existence time.

[0017] Among them, N60K has a molecular weight of about 2,000,000 Daltons and a 2% aqueous solution viscosity of 2,000 to 4,000 cP. It is a polyoxyethylene with the characteristics of large molecular weight, wide range of applications, fast gelation speed, good suspension performance, and good formability.

[0018] Preferably, the disintegrant is one or both of crospovidone and sodium starch glycolate, preferably crospovidone XL.

[0019] Cross-linked polyvinylpyrrolidone is a water-insoluble tablet disintegrant or dissolving agent. Cross-linked polyvinylpyrrolidone can quickly show high capillary activity and excellent hydration ability, and has almost no tendency to gel. In sustained-release preparations, it can be used as a disintegrant, acting as a preparation that quickly absorbs water and swells from gastric juice when entering the stomach, prolonging the retention time of the preparation in the stomach. It is one of the main components for controlling drug dissolution and release.

[0020] Among them, cross-linked polyvinylpyrrolidone XL has the characteristics of wider dosage range and better swelling properties.

[0021] Preferably, the gel is carbomer, and its viscosity is 4000-10000cps. Preferably, the carbomer is 71G.

[0022] Carbomer is a synthetic high molecular weight acrylic acid cross-linked polymer, mainly used as a suspending agent or viscosity increasing agent in liquid or semisolid drug dosage forms. As a hydrophilic gelling agent, it can change (e.g., prolong) the drug release of the dosage form, and can be used in oral preparations, suspensions, tablets, or sustained-release tablets. Carbomer has a viscosity of 4000cps-10000cps, and has the characteristics of high viscosity, wide dosage range, fast gelation speed, and good suspending ability. It is one of the main components for controlling drug dissolution and release, and can prolong the floating existence time of tablets in the solution.

[0023] Among them, Carbomer 71G has good stability and adhesion, good compressibility under low pressure, and good compatibility with other excipients, and can be directly compressed.

[0024] Preferably, the lubricant is one or more of magnesium stearate, sodium stearyl fumarate and silicon dioxide.

[0025] In another aspect, the present invention provides a method for preparing pregabalin gastric floating sustained-release tablets, comprising the following steps:

[0026] S1: Raw material pretreatment: weigh the raw materials according to weight percentage, sieve and size the particles;

[0027] S2: Mixing: mixing the active ingredient, skeleton material, disintegrant and gelling agent to obtain intermediate product 1;

[0028] S3: Total mixing: adding lubricant to the intermediate product 1, mixing, and obtaining the intermediate product 2;

[0029] S4: Tableting: The intermediate product 2 is tableted to obtain pregabalin gastric floating sustained-release tablets.

[0030] Preferably, in step S2, the mixing time is 30 to 60 minutes; in step S3, the mixing time is 5 to 10 minutes.

[0031] In another aspect, the present invention provides a use of pregabalin gastric floating sustained-release tablets in the preparation of a drug for treating epilepsy or peripheral neuropathy.

[0032] The technical principle of the present invention is as follows: the inventors found in the research process that the swelling effect of hydroxypropyl methylcellulose alone is not good, and the swelling effect can be achieved by using polyoxyethylene alone, but it cannot meet the target drug release curve and swelling performance requirements at the same time. When hydroxypropyl methylcellulose and polyoxyethylene are used in combination, the release of the target drug is met while the swelling effect is achieved. The inventors further found that the drug swelling performance of the sustained-release floating tablet obtained by using K15M PHARM and polyoxyethylene is better than that of the sustained-release floating tablet obtained by using K4M PH DC / K100M PH DC and polyoxyethylene. This may be due to the interaction between different polymers-polymers and different polymers-mediums, which improves the gel skeleton structure and the dissolution process of the gel skeleton during the drug release process, which not only improves the in vitro release kinetics of the drug, solves the problem of drug burst release, but also improves the drug swelling performance.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] (1) The pregabalin gastric floating sustained-release tablets prepared by the present invention have a floating time of up to 24 hours, and the tablet skeleton remains relatively intact, and the 24-hour sustained-release rate reaches more than 97%.

[0035] (2) The present invention provides a new method for preparing pregabalin sustained-release tablets, which is simple and easy to operate and has more efficient production.

[0036] (3) The present invention does not use a mixture of polyvinyl acetate and polyvinyl pyrrolidone, thereby avoiding the consequence of sudden release of the drug due to the polyvinyl pyrrolidone mixture being easily soluble in water. DETAILED DESCRIPTION

[0037] The technical solution of the present invention is further described below in conjunction with embodiments.

[0038] Hydroxypropyl methylcellulose K4M: The weight average molecular weight is about 400,000, and the viscosity of a 2% solution is 2700-5040 mPa.s. Purchased from Ashland Benecel TM .

[0039] Hydroxypropyl methylcellulose K15M: The weight average molecular weight is about 575,000, and the viscosity of a 2% solution is 13,500 to 25,200 mPa.s. Purchased from Ashland Benecel TM .

[0040] Hydroxypropyl methylcellulose K100M: The weight average molecular weight is about 1,000,000, and the viscosity of a 2% solution is 75,000 to 140,000 mPa.s. Purchased from Ashland Benecel TM .

[0041] Cross-linked polyvinylpyrrolidone XL: average particle size 100-120μm.

[0042] Cross-linked polyvinylpyrrolidone XL-10: average particle size 25-35μm.

[0043] Polyoxyethylene WSR N12K: average molecular weight is 1,200,000, 2% aqueous solution viscosity is 400-800 cP. Purchased from DOW.

[0044] Polyoxyethylene WSR N60K: average molecular weight is 2,000,000, 2% aqueous solution viscosity is 2,000-4,000 cP. Purchased from DOW.

[0045] Polyoxyethylene WSR 301: average molecular weight is 4,000,000, 1% aqueous solution viscosity is 1,650-5,500 cP. Purchased from DOW.

[0046] Carbomer 71G: purchased from Noveon, USA.

[0047] Example 1 Preparation of Pregabalin Gastric Floating Sustained-Release Tablets

[0048] 1. Preparation method

[0049] (1) Raw material pretreatment: sieve and granulate an appropriate amount of raw materials for later use;

[0050] (2) Mixing: Weigh each raw material and auxiliary material according to the prescription amount, add the raw materials and auxiliary materials except magnesium stearate into the mixer in sequence, and mix for 30 minutes after adding, to obtain intermediate product 1;

[0051] (3) Total mixing: After the mixing is completed, add the prescribed amount of magnesium stearate to the intermediate product 1 and mix for 8 minutes to obtain the intermediate product 2;

[0052] (4) Tablet pressing: The tablet weight range is controlled according to the theoretical tablet weight. The tablet weight difference is controlled within ±5% and the hardness is between 60 and 120N.

[0053] The proportions of the raw materials are shown in Table 1.

[0054] Table 1 Prescriptions with different raw material ratios

[0055]

[0056]

[0057] 2. In vitro release test

[0058] According to the second method (paddle method) of the dissolution and release determination method of the fourth appendix of the 2020 edition of the Chinese Pharmacopoeia, a sinker was added to carry out an in vitro release experiment on the pregabalin sustained-release tablets and the reference preparation (Control Example 1) prepared in the embodiment. 900ml of 0.06mol / L hydrochloric acid solution (pH=1.2) was used as the release medium, the number of revolutions was 50rpm, the temperature was 37±0.5°C, and 10ml was sampled at 1, 2, 4, 6, 8, 9, 10, 12, 16 and 24h, respectively, and the HPLC was used for detection, and the cumulative release was calculated. The similarity factor f2 values ​​of the reference preparation (Control Example 1) and prescriptions 1-4 were calculated based on the in vitro release data of 1, 4, 9, and 16h. When the similarity factor f2≥50, the two release curves can be considered to be similar. The results are shown in Table 2.

[0059] Table 2 Drug release of different formulations

[0060]

[0061] 3. Drug swelling and floating performance test

[0062] Using 900 ml of 0.06 mol / L hydrochloric acid solution (pH=1.2) as the medium, the rotation speed is 50 rpm, the temperature is 37±0.5°C, take a piece and put it into the cup to observe its swelling and floating phenomena. Detect the swelling and floating properties of the drugs in prescriptions 1-4.

[0063] Reference: The sample floated on the liquid surface after being put in, and was still suspended on the liquid surface after 24 hours. The tablet swelled significantly, and there was a small amount of particles at the bottom of the cup.

[0064] Prescription 1: After the sample was placed in the dissolution medium, it quickly sank to the bottom and floated to the liquid surface after about 4 hours. After 16 hours, it was found that the tablet skeleton was destroyed and most of the tablets had dissolved.

[0065] Prescription 2: After the sample was placed in the dissolution medium, it quickly floated on the liquid surface, began to swell after about 6 hours, and still floated on the liquid surface at the end of 24 hours. The tablet skeleton remained relatively intact.

[0066] Prescription 3: After the sample was placed in the dissolution medium, it quickly floated on the liquid surface, began to swell after about 6 hours, and was suspended in the lower part of the solution after 22 hours. It failed to remain floating on the liquid surface for 24 hours, but the tablet skeleton remained intact and the tablet swelled significantly.

[0067] Prescription 4: After the sample was placed in the dissolution medium, it quickly floated on the liquid surface. It began to swell after about 6 hours. After 16 hours, it was found that the tablet skeleton was destroyed. After 24 hours, about half of the tablets were dissolved, and the remaining tablets floated on the liquid surface.

[0068] In prescriptions 2-4, different types of polyoxyethylene are added, including WSR N60K, WSR 301 and WSR N12K. It can be seen from the results that different types of polyoxyethylene will affect the drug release rate. Prescription 2 uses WSR N60K. After 24 hours, the skeleton remains intact and floats on the liquid surface, and its sustained release effect is the best; Prescription 3 uses WSR 301, which has good swelling performance, but long-term swelling may cause excessive water absorption, resulting in a decrease in the suspension performance of the tablet; Prescription 4 uses WSR N12K, which has general swelling properties. This model has a small molecular weight, and long-term swelling may cause the molecular chain to break into small molecular compounds. Small molecular compounds are easily soluble in water and destroy the integrity of the skeleton material. The larger the molecular weight of polyoxyethylene, the better the swelling and viscosity. The present invention selects a suitable model to achieve the desired effect.

[0069] In prescription 1, mannitol, a diluent, was added, and disintegrant was omitted. It can be seen that the drug skeleton was destroyed after 16 hours. Its effect was obviously not as good as that of prescription 2. This is because mannitol, a diluent, is partially soluble in water, and the skeleton retention may not be so good after adding the diluent. If cross-linked polyvinylpyrrolidone is added, it will disintegrate faster.

[0070] Example 2 Preparation of Pregabalin Gastric Floating Sustained-Release Tablets

[0071] 1. Pregabalin gastric floating sustained-release tablets were prepared according to the method of Example 1. The proportions of the raw materials are shown in Table 3.

[0072] Table 3 Prescriptions with different raw material ratios

[0073]

[0074]

[0075] 2. In vitro release test

[0076] The in vitro release experiment was carried out according to the method in Example 1, and the release curve data are shown in Table 4.

[0077] Table 4 Drug release of different formulations

[0078]

[0079] 3. Drug swelling and floating performance test

[0080] The drug swelling and floating performance test was carried out according to the method of Example 1, and the results are as follows:

[0081] Prescription 5: After the sample was placed in the dissolution medium, it quickly floated on the liquid surface. It began to swell after about 6 hours and was still floating on the liquid surface at the end of 24 hours. The tablet skeleton remained intact and was in a soft gel state.

[0082] Prescription 6: After the sample was placed in the dissolution medium, it quickly floated on the liquid surface. It began to swell after about 6 hours and was still floating on the liquid surface at the end of 24 hours. The tablet skeleton remained intact and was in a soft gel state.

[0083] Prescription 7: After the sample was placed in the dissolution medium, it quickly floated on the liquid surface. It began to swell after about 6 hours and was still floating on the liquid surface at the end of 24 hours. The tablet skeleton was destroyed and about two-thirds of it was dissolved.

[0084] Prescription 8: After the sample was placed in the dissolution medium, it quickly floated on the liquid surface. It began to swell after about 6 hours and was still floating on the liquid surface at the end of 24 hours. The tablet skeleton was destroyed and about two-thirds of it was dissolved.

[0085] In prescription 5, the disintegrant is cross-linked polyvinylpyrrolidone XL-10, and in prescription 6, the disintegrant is sodium starch glycolate, and the effects of drug release and drug swelling are not much different. It can be seen that the effects of cross-linked polyvinylpyrrolidone and sodium starch glycolate in disintegrants are similar. In prescriptions 6-8, different types of hydroxypropyl methylcellulose are added, including hydroxypropyl methylcellulose K4M, K15M, and K100M. It can be seen from the results that prescription 6 still floats on the page after 24 hours, and the skeleton remains intact, and its swelling performance and floating performance are the best. Although the drug tablets in prescriptions 7 and 8 float on the page, the skeleton structure is destroyed and the sustained release effect is deteriorated. It can be seen that K15M PHARM has the best effect.

[0086] Example 3 Preparation of Pregabalin Gastric Floating Sustained-Release Tablets

[0087] 1. Pregabalin gastric floating sustained-release tablets were prepared according to the method of Example 1. The proportions of the raw materials are shown in Table 5.

[0088] Table 5 Prescriptions with different raw material ratios

[0089]

[0090] 2. In vitro release test

[0091] The in vitro release experiment was carried out according to the method in Example 1, and the release curve data are shown in Table 6.

[0092] Table 6 Drug release of different formulations

[0093]

[0094]

[0095] 3. Drug swelling and floating performance test:

[0096] The drug swelling and floating performance test was carried out according to the method of Example 1, and the results are as follows:

[0097] Prescription 9: After the sample was placed in the dissolution medium, it quickly floated on the liquid surface, began to swell after about 7 hours, and still floated on the liquid surface at the end of 24 hours, and the tablet skeleton remained intact. Compared with Prescription 2, reducing the amount of disintegrant cross-linked polyvinylpyrrolidone has little effect on product quality.

[0098] Prescription 10: After the sample was placed in the dissolution medium, it quickly floated on the liquid surface, began to swell after about 5 hours, and still floated on the liquid surface at the end of 24 hours. The tablet skeleton remained intact, and there was a small amount of particles at the bottom of the cup. Compared with Prescription 2, increasing the amount of disintegrant crospovidone slightly improved the product quality, but the effect was not significant.

[0099] Prescription 11: After the sample was placed in the dissolution medium, it quickly floated on the liquid surface, began to swell after about 6 hours, and still floated on the liquid surface at the end of 24 hours, with particles at the bottom of the cup. Compared with Prescription 2, reducing the amount of gelling agent has little effect on product quality, but too little dosage will accelerate the dissolution rate of the drug and affect the sustained-release effect.

[0100] Prescription 12: After the sample was placed in the dissolution medium, it quickly floated on the liquid surface, began to swell after about 6 hours, and still floated on the liquid surface at the end of 24 hours, with particles at the bottom of the cup. Compared with Prescription 2, increasing the amount of gelling agent has little effect on product quality, but excessive use will slow down the drug dissolution rate.

[0101] Example 4 Preparation of Pregabalin Gastric Floating Sustained-Release Tablets

[0102] 1. Pregabalin gastric floating sustained-release tablets were prepared according to the method of Example 1. The proportions of the raw materials are shown in Table 7.

[0103] Table 7 Prescriptions with different raw material ratios

[0104]

[0105] 2. An in vitro release experiment was performed according to the method in Example 1. The release curve data are shown in Table 8.

[0106] Table 8 Drug release of different formulations

[0107]

[0108]

[0109] 3. Carry out drug swelling and floating performance test according to the method of Example 1:

[0110] Prescription 13: After the sample is placed in the dissolution medium, it quickly floats on the liquid surface. It begins to swell after about 6 hours. At the end of 24 hours, it is still floating on the liquid surface, and there are particles at the bottom of the cup.

[0111] Prescription 14: After the sample is placed in the dissolution medium, it quickly floats on the liquid surface. It begins to swell after about 6 hours. At the end of 24 hours, it is still floating on the liquid surface, and there are particles at the bottom of the cup.

[0112] The release rate of the drug and the swelling and floating properties of the drug under different K15M PHARM and WSR N60K ratios. It can be seen that the drug still has good sustained release and swelling and floating properties under different ratios.

[0113] Prescription 15: After the sample was placed in the dissolution medium, it quickly floated on the liquid surface and began to swell after about 4 hours. After 16 to 18 hours, the tablets were suspended in the middle of the dissolution cup or near the bottom of the cup. A large number of particles were found at the bottom of the cup, which might be caused by the shedding of other excipients wrapped in polyethylene oxide.

[0114] In addition, the inventors found that when the drug does not contain fillers or other skeleton materials and only has hydroxypropyl methylcellulose as the skeleton material, the swelling effect is not good; and the dosage of hydroxypropyl methylcellulose exceeds the standard, which does not conform to the conventional method of solid preparations and cannot be made into a preparation that meets the requirements.

[0115] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution of the present invention, which should be included in the scope of the claims of the present invention.

Claims

1. A pregabalin gastric floating sustained-release tablet, characterized in that: Its components and weight percentages are: Active ingredient 7-33% Frame material 50-86% Disintegrant 3-15% Gel 2-10% Lubricant 0.25-3% The active ingredient is pregabalin and its pharmaceutically acceptable salt; the skeleton material is hypromellose K15M and polyoxyethylene N60K, and the mass ratio of the hypromellose K15M and polyoxyethylene N60K is 5:16-64; the disintegrant is one or two of cross-linked polyvinylpyrrolidone XL and sodium starch glycolate; the gelling agent is carbomer 71G, and its viscosity is 4000-10000 cps; the lubricant is one or more of magnesium stearate, sodium stearyl fumarate and silicon dioxide.

2. A method for preparing a pregabalin gastric floating sustained-release tablet according to claim 1, comprising the following steps: S1: Raw material pretreatment: weigh the raw materials according to weight percentage, sieve and size the particles; S2: Mixing: mixing the active ingredient, skeleton material, disintegrant and gelling agent to obtain intermediate product 1; S3: Total mixing: adding lubricant to the intermediate product 1, mixing, and obtaining the intermediate product 2; S4: Tableting: The intermediate product 2 is tableted to obtain pregabalin gastric floating sustained-release tablets.

3. The method for preparing a pregabalin gastric floating sustained-release tablet according to claim 2, characterized in that: In step S2, the mixing time is 30 to 60 minutes; in step S3, the mixing time is 5 to 10 minutes.

4. Use of the pregabalin gastric floating sustained-release tablets according to any one of claims 1 to 3 in the preparation of a drug for treating epilepsy or peripheral neuropathy.

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