Multi-release sinomenine hydrochloride sustained-release pellet preparation

Abstract

The invention provides a multi-release sinomenine hydrochloride sustained-release pellet preparation. The pellet preparation comprises a sustained-release pellet and an enteric-coated pellet in a mass ratio of 1: (1-5), the sustained-release pellet sequentially comprises a pellet core, a medicine carrying layer and a sustained-release layer from inside to outside, the enteric-coated pellet sequentially comprises a pellet core, a medicine carrying layer, a sustained-release layer, an isolating layer and an enteric-coated layer from inside to outside. The multi-release sinomenine hydrochloride sustained-release pellet preparation disclosed by the invention is formed by mixing a sustained-release pellet and an enteric-coated pellet, and the dissolution stability of the pellet preparation is good.

Description

Technical Field

[0001] The invention belongs to the field of biomedicine, and in particular relates to a multiple-release sinomenine hydrochloride sustained-release pellet preparation and a preparation method thereof. Background Art

[0002] Rheumatoid arthritis is a chronic disease with significant pain and a long course of disease. The elderly are the main patients with rheumatoid arthritis. Studies have shown that as patients age, gastric emptying time becomes longer. This is because the peristalsis and emptying function of the stomach may gradually weaken during aging, resulting in a longer retention time of food and liquid in the stomach. However, when SH (sinomenine hydrochloride) preparations stay in the patient's stomach for too long, two consequences may occur: (1) Since SH has obvious gastrointestinal side effects, when a large amount of SH in ordinary preparations is dissolved in the stomach, it may cause side effects; (2) For enteric-coated preparations, too long stomach retention time may cause SH to fail to dissolve smoothly, resulting in the patient's pain not being relieved in time. "Suwen" records that "when the disease occurs and the deficiency is insufficient, the symptoms should be treated first and the root cause should be treated later." In order to reduce the side effects of SH in different patient populations, and at the same time give full play to the treatment concept of treating the symptoms first and the root cause later in traditional Chinese medicine, and prevent the patient's condition from being delayed, it is of great significance to develop multiple release SH sustained-release micropellets using multiple release technology. Summary of the invention

[0003] In view of this, the present invention aims to overcome the defects in the prior art and proposes a multiple-release sinomenine hydrochloride sustained-release pellet preparation.

[0004] To achieve the above object, the technical solution of the present invention is achieved as follows:

[0005] A multiple-release sinomenine hydrochloride sustained-release pellet preparation, the pellet preparation comprising sustained-release pellets and enteric-coated pellets in a mass ratio of 1:1-5;

[0006] The sustained-release pellets include a pellet core, a drug-carrying layer and a sustained-release layer from the inside to the outside;

[0007] The enteric-coated micropill comprises a pellet core, a drug-carrying layer, a sustained-release layer, a separation layer and an enteric-coated layer in sequence from the inside to the outside.

[0008] Furthermore, the sustained-release layer of the enteric-coated microcapsules comprises a pore-forming agent, a plasticizer and a matrix in a mass ratio of 5-17:10:100; the mass concentration of the matrix in the coating solution of the sustained-release layer is 4-5%.

[0009] Preferably, the sustained-release layer of the enteric-coated microcapsules comprises a pore-forming agent, a plasticizer and a matrix in a mass ratio of 10:10:100; the mass concentration of the matrix in the coating solution of the sustained-release layer is 4%.

[0010] Furthermore, the porogen is PVP K30 (polyvinyl pyrrolidone, model K30); the plasticizer is TEC (triethyl citrate); and the matrix is ​​EC 45 (ethyl cellulose, model 45).

[0011] Furthermore, the isolation layer of the enteric-coated microcapsules comprises an anti-adhesive agent and an adhesive agent in a mass ratio of 30-45:100; the adhesive agent is HPMC E5 (abbreviation of hydroxypropyl methylcellulose, model E5); the anti-adhesive agent is talcum powder; and the weight gain of the isolation layer of the enteric-coated microcapsules is 5-10%.

[0012] Preferably, the isolation layer of the enteric-coated micropellets includes an anti-adhesive agent and an adhesive in a mass ratio of 45:100; the isolation layer of the enteric-coated micropellets has a weight gain of 5%. Weight gain means that the components of the layer are increased synchronously in mass ratio.

[0013] Furthermore, the enteric layer of the enteric pellets includes a nonionic surfactant, a plasticizer, an anti-adhesive agent and an enteric material in a mass ratio of 2:10:5:100; the weight gain of the enteric layer of the enteric pellets is 30-40%. The weight gain means that the components of the layer increase synchronously in mass ratio.

[0014] Preferably, the enteric layer weight gain of the enteric-coated micropellets is 30%.

[0015] Further, the nonionic surfactant is Tween 80; the plasticizer is TEC; the anti-adhesive agent is GMS (glyceryl monostearate); the enteric material is at least one of EUDRAGIT RL, EUDRAGIT RS, EUDRAGIT L or EUDRAGIT S (EUDRAGIT is the trade name of a series of polymers produced by Evonik, mainly used in pharmaceutical preparations. The main components of these polymers are copolymers of acrylic acid and its esters); preferably, the enteric material is L 30D-55.

[0016] Furthermore, the drug-carrying layer of the sustained-release microcapsules comprises an adhesive and sinomenine hydrochloride in a mass ratio of 9-17:100; the mass concentration of sinomenine hydrochloride in the coating solution of the drug-carrying layer is 6-9%; the adhesive is HPMC E5; the drug-carrying layer of the sustained-release microcapsules is the same as the drug-carrying layer of the enteric-coated microcapsules.

[0017] Preferably, the drug-carrying layer of the sustained-release microcapsules comprises a binder and sinomenine hydrochloride in a mass ratio of 17:100; the mass concentration of sinomenine hydrochloride in the coating solution of the drug-carrying layer is 7.5%.

[0018] Furthermore, the sustained-release layer of the sustained-release microcapsules comprises a pore-forming agent, a plasticizer and a matrix in a mass ratio of 5-17:10:100; the mass concentration of the matrix in the coating solution of the sustained-release layer is 3-17%.

[0019] Preferably, the sustained-release layer of the sustained-release microcapsules comprises a pore-forming agent, a plasticizer and a matrix in a mass ratio of 17:10:100; the mass concentration of the matrix in the coating solution of the sustained-release layer is 17%.

[0020] Furthermore, the porogen is PVP K30; the plasticizer is TEC; and the matrix is ​​EC 45.

[0021] Furthermore, the core of the sustained-release microcapsules is the same as the core of the enteric-coated microcapsules; the core of the sustained-release microcapsules is the core of the MCC microcapsules; the mass of the core is 150 g, and the particle size is 400-700 μm.

[0022] Compared with the prior art, the present invention has the following advantages:

[0023] The multiple-release sinomenine hydrochloride sustained-release pellet preparation of the present invention is prepared by mixing sustained-release pellets with enteric-coated pellets. During storage, the pellet preparation is subjected to a dissolution test, and the results show that the dissolution behavior of the preparation is stable, and the standard deviation of the drug release rate at each time point of the dissolution curve is less than 2%. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 It is a binary image of the sustained-release layer prescription described in Example 1 of the present invention: wherein, Figure A is Example 1, Figure B is Example 2, and Figure C is Example 3;

[0025] Figure 2 The drug release curve of the SH enteric-coated pellets with increased weight of the isolation layer described in Example 1 of the present invention;

[0026] Figure 3 The results of the investigation on the acid resistance (pH=1.2) of the SH enteric-coated pellets with increased enteric layer weight as described in Example 1 of the present invention;

[0027] Figure 4 The results of the investigation on the acid resistance (pH=6.8) of the SH enteric-coated pellets with increased enteric layer weight as described in Example 1 of the present invention;

[0028] Figure 5 The dissolution curve of the SH enteric-coated pellets with increased enteric layer weight as described in Example 1 of the present invention;

[0029] Figure 6 This is the dissolution curve of the multiple-release SH sustained-release pellets described in Example 1 of the present invention during a storage period of 3 months;

[0030] Figure 7 The scanning electron microscope images of the sustained-release pellets described in Example 1 of the present invention are shown in FIG. AD, FIG. EG, and FIG. H are images of the overall morphology of the pellets; FIG. H is an image of the cross-sectional morphology of the pellets;

[0031] Figure 8 The following are scanning electron microscope images of the enteric-coated micropellets described in Example 1 of the present invention: wherein, the AD image is an overall morphology image of the micropellets; the EG image is a surface morphology image of the micropellets; and the H image is a cross-sectional morphology image of the micropellets;

[0032] Fig. 9 This is the infrared spectra of the SH, MCC pellet cores, sustained-release pellets, and enteric-coated pellets described in Example 1 of the present invention. DETAILED DESCRIPTION

[0033] Unless otherwise defined, the technical terms used in the following examples have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods, unless otherwise specified, are all conventional methods.

[0034] Materials and experimental equipment

[0035] SH (purity > 98%, Changsha Shanghe Biotechnology Co., Ltd., China); MCC micropellets (Asahi Kasei Corporation, Japan); HPMC E5 (Shanghai Colorcon Coating Technology Co., Ltd., China); EC 45 (Anhui Shanhai Pharmaceutical Excipients Co., Ltd., China); PVP K30 (Anhui Shanhai Pharmaceutical Excipients Co., Ltd., China); TEC (Tianjin Fengchuan Chemical Reagent Technology Co., Ltd., China). L 30D-55 (Shanghai Changwei Pharmaceutical Excipients Technology Co., Ltd., China); Tween 80 (Wuxi Yatai United Chemical Co., Ltd., China); Glyceryl monostearate (GMS) (Tianjin Fengchuan Chemical Reagent Technology Co., Ltd., China); Talc (Tianjin Fengchuan Chemical Reagent Technology Co., Ltd., China); Potassium dihydrogen phosphate (Sinopharm Chemical Reagent Co., Ltd., China); Magnesium stearate (Anhui Shanhai Pharmaceutical Excipients Co., Ltd., China); Deionized water was prepared using a Milli-Q ultrapure water system (Millipore Corporation, USA).

[0036] Bottom-spray fluidized bed; BT-2600 laser particle size distribution analyzer (Dandong Better Instrument Co., Ltd., China); Cary8454 UV-visible spectrophotometer (Agilent Technologies, Inc., USA); S-4800 field emission gun scanning electron microscope (Hitachi, Japan); IRTracer-100 Fourier transform infrared spectrometer (Shimadzu Corporation, Japan); BT-1600 image particle analysis system (Dandong Better Instrument Co., Ltd., China); AL204 electronic balance (Mettler-Toledo International AG, Switzerland); AB135-S electronic balance (Mettler-Toledo International AG, Switzerland).

[0037] The present invention will be described in detail below with reference to the embodiments.

[0038] Example 1

[0039] A multiple-release sinomenine hydrochloride sustained-release pellet preparation, the pellet preparation comprising sustained-release pellets and enteric-coated pellets in a mass ratio of 1:2; the sustained-release pellets sequentially comprise a pellet core, a drug-carrying layer and a sustained-release layer from the inside to the outside; the enteric-coated pellets sequentially comprise a pellet core, a drug-carrying layer, a sustained-release layer, an isolation layer and an enteric-coated layer from the inside to the outside.

[0040] The sustained-release layer of the enteric-coated micropellets includes PVP K30, TEC and EC 45 in a mass ratio of 10:10:100; the mass concentration of the matrix in the coating solution of the sustained-release layer is 4%;

[0041] The isolation layer of the enteric-coated micropellets comprises talcum powder and HPMC E5 in a mass ratio of 45:100; the weight gain of the isolation layer of the enteric-coated micropellets is 5%;

[0042] The enteric layer of the enteric pellets includes non-Tween 80, TEC, GMS and L 30D-55; the enteric layer weight gain of the enteric-coated pellets is 30%.

[0043] The drug-carrying layer of the sustained-release micropellets includes HPMC E5 and SH in a mass ratio of 17:100; the mass concentration of SH in the coating solution of the drug-carrying layer is 7.5%;

[0044] The sustained-release layer of the sustained-release micropellets comprises PVP K30, TEC and EC 45 in a mass ratio of 17:10:100; the mass concentration of EC 45 in the coating solution of the sustained-release layer is 17%.

[0045] The core of the sustained-release micro-pellets is the same as the core of the enteric-coated micro-pellets; the core of the sustained-release micro-pellets is the core of the MCC micro-pellets; the mass of the core is 150 g, and the particle size is 400-700 μm.

[0046] The preparation method of the coating solution of the drug-carrying layer is as follows: firstly prepare the HPMC E5 aqueous solution, and after 12 hours, prepare the SH aqueous solution, and then slowly pour the SH aqueous solution into the HPMC E5 aqueous solution under stirring, and prepare the drug-carrying layer coating solution after sufficient stirring.

[0047] Preparation method of sustained-release layer coating solution: pour EC 45, PVP K30 and TEC into anhydrous ethanol in sequence, mix them evenly to obtain sustained-release layer coating solution.

[0048] Preparation method of isolation layer coating liquid: first prepare HPMC E5 aqueous solution, after 12 hours, slowly pour talcum powder into HPMC E5 aqueous solution, and prepare isolation layer coating liquid after fully stirring.

[0049] Preparation method of enteric coating liquid: heat pure water to 70-80℃, take out some pure water, add Tween 80, TEC, GMS to it, stir continuously for 10 minutes to obtain a suspension with a solid content of about 15%, add the remaining pure water to the suspension, stir continuously until the suspension cools to room temperature, and then pour it into L 30D-55 dispersion, gently stir, and pass through a 0.45 mm sieve to obtain the enteric layer coating solution.

[0050] According to the dosage of 60 mg, the sustained-release pellets and the enteric-coated pellets were prepared in a ratio of 1:2 to obtain multiple-release SH sustained-release pellets.

[0051] Example 2

[0052] The only difference from Example 1 is that the mass ratio of HPMC E5 to SH in the drug-loading layer of the sustained-release pellets is 13:100.

[0053] Example 3

[0054] The only difference from Example 1 is that the mass concentration of SH in the drug-loading layer coating solution of the sustained-release micropellets is 9%.

[0055] The quality parameters of the micropellets in Examples 1-3 are shown in Table 1.

[0056] Table 1 Quality parameters of pellets with different drug loading layer prescriptions

[0057]

[0058] Note: X1: HPMC E5 to SH ratio (%); X2: SH mass concentration in coating solution (%); Y1: pellet yield (%); Y2: SH encapsulation efficiency (%); Y3: RSD value of SH content distribution uniformity (%, n = 6); Y4: roundness; Y5: coating time (min); Y6: Span.

[0059] Figure 1 It is an image of some individuals in the micropills of Examples 1-3 after binarization. Content uniformity is an extremely important quality evaluation index of micropills, which directly determines the dosage stability of the final preparation. Therefore, the present invention uses it as the most critical indicator in prescription screening. It can be found from Table 1 that the RSD value of distribution uniformity of Example 1 is the lowest, which is 3.15%, and the other quality attributes of the micropills are at a high level. Therefore, this prescription is used as the optimal drug-carrying layer prescription of the micropills.

[0060] Example 4

[0061] The only difference from Example 1 is that the mass ratio of PVP K30, TEC and EC45 in the sustained-release layer of the sustained-release micropellets is 15:10:100; and the mass concentration of EC 45 in the coating solution of the sustained-release layer is 2.5%.

[0062] The pellets obtained in Example 4 were able to achieve sustained release of the drug for 4 h. After using the bottom-spray fluidized bed, a sudden release of the drug occurred, indicating that the formulation of Example 4 was not applicable.

[0063] Example 5

[0064] The only difference from Example 1 is that the mass ratio of talc to HPMC E5 in the isolation layer of the enteric-coated pellets is 30:100.

[0065] Example 6

[0066] The only difference from Example 1 is that the weight gain of the isolation layer of the enteric-coated micropellets is 10%.

[0067] Example 7

[0068] The only difference from Example 1 is that the mass ratio of talc to HPMC E5 in the isolation layer of the enteric-coated micropellets is 30:100; and the weight gain of the isolation layer of the enteric-coated micropellets is 10%.

[0069] Example 8

[0070] The only difference from Example 1 is that the weight gain of the isolation layer of the enteric-coated micropellets is 0%.

[0071] Table 2 Operability results of different isolation layer prescriptions

[0072]

[0073]

[0074] Table 3 In vitro dissolution results of weighted pellets with different isolation layers

[0075]

[0076] After setting two common levels for the dosage ratio of talc and HPMC E5 and the weight gain of the isolation layer, an isolation layer coating test was conducted. The operability results of the test are shown in Table 2-3. Based on the results, the dosage ratio of talc and HPMC E5 was set to 45%. Then, the isolation layer weight gain was screened based on the drug dissolution behavior. Table 2 lists the cumulative release rates of SH of the two isolation layer weight gain micropellets during the dissolution process. Figure 2 The dissolution curve of the microcapsules is shown. The results show that the dissolution curve of the microcapsules did not change significantly after the isolation layer coating. In addition, according to the standard deviation of the SH cumulative release rate, it can be found that the dissolution stability of the microcapsules with an isolation layer weight gain of 5% is higher. The reason is speculated to be that the drug release mechanism has changed from membrane-controlled to membrane-controlled-gel layer diffusion, so that the drug release is more stable. Based on the above analysis, the isolation layer prescription of enteric-coated microcapsules is 45% of talcum powder and HPMC E5, and the isolation layer weight gain is 5%.

[0077] Example 9

[0078] The only difference from Example 1 is that the enteric layer of the enteric-coated micropellets has a weight increase of 35%.

[0079] Example 10

[0080] The only difference from Example 1 is that the enteric layer of the enteric-coated micropellets has a weight increase of 40%.

[0081] The pellets were placed in a hydrochloric acid solution (pH = 1.2) for 4 hours to test their acid resistance. Figure 3 As shown. The cumulative SH release rate of the three micropellets at the 4th hour of dissolution was less than 10%, indicating that the three micropellets all had good acid resistance. In order to reduce the thickness of the enteric layer, the present invention selected micropellets with an enteric layer weight gain of 30% and 35% for subsequent research. After the hydrochloric acid solution was replaced with a phosphate buffer solution (pH = 6.8), Figure 4-5 The results of the acid resistance test and dissolution of the two enteric-coated microcapsules were shown respectively. The results showed that the acid resistance of the two microcapsules was good, and the drug dissolution curve of the microcapsules met the set target, that is, they could maintain sustained release for 8 hours in a phosphate buffer with a pH of 6.8. In order to reduce the thickness of the enteric layer coating film, the weight gain of the enteric layer was finally set to 30%.

[0082] Drug stability assessment:

[0083] In vitro dissolution test was conducted on Example 1. A hydrochloric acid solution with a pH of 1.2 was used for the first 4 hours of the dissolution process, and a phosphate buffer solution with a pH of 6.8 was used for the last 8 hours. The preparation was stored at 4°C and room temperature for 3 months. Samples were taken at the end of the first, second, and third months, and then the dissolution test was conducted using the same method. The results are as follows: Figure 6 As shown in the figure, it can be seen that the dissolution stability of the micropellets is good, and the drug dissolution curve has not changed significantly within 3 months.

[0084] Characterization of the physicochemical properties of pellets:

[0085] The physical morphology of sustained-release pellets was analyzed by scanning electron microscopy. Figure 7 It can be seen that the microcapsules have good roundness, the boundaries between the pellet core, the drug-loaded layer and the sustained-release layer are obvious, the drug-loaded layer has a tight texture, good adhesion, and the sustained-release membrane is not damaged.

[0086] At the same time, the morphology of enteric-coated pellets was analyzed, such as Figure 8 As shown. It can be seen that the enteric-coated micropellets have good roundness and a smooth surface without obvious depressions. When the micropellet surface is magnified 40,000 times, the enteric layer material with a mesh structure can be clearly observed. From the cross-sectional image, it can be observed that the pellet core, drug-loaded layer, sustained-release layer, isolation layer and enteric layer are clearly demarcated, and the drug-loaded layer, sustained-release layer and isolation layer are tightly bonded without gaps.

[0087] The infrared spectrum of SH contains 6 characteristic peaks. Fig. 9 The infrared spectra of SH, MCC pellets, sustained-release pellets and enteric-coated pellets are shown in Figure 2. It can be seen that the two sustained-release pellets contain all the characteristic peaks of SH and no impurity peaks, which indicates that the chemical stability between the components during the coating process is good.

[0088] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A multiple-release sinomenine hydrochloride sustained-release pellet preparation, characterized in that: The pellet preparation comprises sustained-release pellets and enteric-coated pellets in a mass ratio of 1:1-5; The sustained-release pellets include a pellet core, a drug-carrying layer and a sustained-release layer from the inside to the outside; The enteric-coated micropill comprises a pellet core, a drug-carrying layer, a sustained-release layer, a separation layer and an enteric-coated layer in sequence from the inside to the outside.

2. The multiple-release sinomenine hydrochloride sustained-release pellet preparation according to claim 1, characterized in that: The sustained-release layer of the enteric-coated microcapsules comprises a pore-forming agent, a plasticizer and a matrix in a mass ratio of 5-17:10:100; the mass concentration of the matrix in the coating solution of the sustained-release layer is 4-5%.

3. The multiple-release sinomenine hydrochloride sustained-release pellet preparation according to claim 2, characterized in that: The porogen is PVP K30; the plasticizer is TEC; and the matrix is ​​EC 45.

4. The multiple-release sinomenine hydrochloride sustained-release pellet preparation according to claim 1, characterized in that: The isolation layer of the enteric-coated micropills comprises an anti-adhesive agent and an adhesive agent in a mass ratio of 30-45:100; the adhesive agent is HPMC E5; the anti-adhesive agent is talcum powder; and the weight gain of the isolation layer of the enteric-coated micropills is 5-10%.

5. The multiple-release sinomenine hydrochloride sustained-release pellet preparation according to claim 1, characterized in that: The enteric layer of the enteric micropill comprises a nonionic surfactant, a plasticizer, an anti-adhesive agent and an enteric material in a mass ratio of 2:10:5:100-125; the weight gain of the enteric layer of the enteric micropill is 30-40%.

6. The multiple-release sinomenine hydrochloride sustained-release pellet preparation according to claim 5, characterized in that: The nonionic surfactant is Tween 80; the plasticizer is TEC; the anti-adhesive agent is GMS; the enteric material is at least one of EUDRAGIT RL, EUDRAGIT RS, EUDRAGIT L or EUDRAGIT S; preferably, the enteric material is L 30D-55.

7. The multiple-release sinomenine hydrochloride sustained-release pellet preparation according to claim 1, characterized in that: The drug-carrying layer of the sustained-release microcapsules comprises an adhesive and sinomenine hydrochloride in a mass ratio of 9-17:100; the mass concentration of sinomenine hydrochloride in the coating solution of the drug-carrying layer is 6-9%; the adhesive is HPMC E5; the drug-carrying layer of the sustained-release microcapsules is the same as the drug-carrying layer of the enteric-coated microcapsules.

8. The multiple-release sinomenine hydrochloride sustained-release pellet preparation according to claim 1, characterized in that: The sustained-release layer of the sustained-release micropill comprises a pore-forming agent, a plasticizer and a matrix in a mass ratio of 5-17:10:100; the mass concentration of the matrix in the coating solution of the sustained-release layer is 3-17%.

9. The multiple-release sinomenine hydrochloride sustained-release pellet preparation according to claim 8, characterized in that: The porogen is PVP K30; the plasticizer is TEC; and the matrix is ​​EC 45.

10. The multiple-release sinomenine hydrochloride sustained-release pellet preparation according to claim 1, characterized in that: The core of the sustained-release micro-pellets is the same as the core of the enteric-coated micro-pellets; the core of the sustained-release micro-pellets is the core of the MCC micro-pellets; the mass of the core is 150 g, and the particle size is 400-700 μm.

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