Naringin pH / enzyme double-response colon-targeted dropping pill and preparation method thereof

Abstract

The invention discloses a naringin pH / enzyme double-response type colon-targeted dropping pill, and belongs to the technical field of biological pharmacy. The enteric-coated dropping pill comprises an enteric-coated layer coating and a pill core in a mass ratio of (5-9): (12-16), wherein the enteric layer coating is prepared from the following raw materials in parts by weight: 20 to 40 parts of polyacrylic resin III, 10 to 20 parts of talcum powder, 2 to 4 parts of polyethylene glycol 6000, 10 to 20 parts of resistant starch and 200 to 400 parts of ethanol; the pellet core comprises naringin and a matrix in a mass ratio of 1: (2-4).

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a naringin pH / enzyme dual-responsive colon-targeted dropping pill and a preparation method thereof. Background Art

[0002] Ulcerative colitis (UC) is a type of chronic nonspecific inflammation involving the rectal and colonic mucosa. It is a type of inflammatory bowel disease (IBD). This type of disease can be caused by a variety of factors. The lesions are mainly located in the intestinal mucosa and submucosa, which often lead to cell barrier dysfunction. The clinical symptoms are abdominal pain, diarrhea, mucous blood in the stool, and the course of the disease is often prolonged. In severe cases, it may even cause intestinal perforation and induce colorectal cancer. UC is difficult to cure and is prone to recurrence. About 15% of patients will experience an invasive course and develop colon or rectal cancer. It has always been considered a refractory disease of the digestive system, and the incidence rate is increasing year by year worldwide. There is currently no specific drug for the treatment of UC on the market. The main clinical treatment strategies for UC include surgical treatment, immunosuppression, and protection of the intestinal mucosal mechanical barrier. In terms of drug use, corticosteroids, sulfonamides, thiopurines, etc. are mostly used, but patients who use these drugs for a long time are prone to adverse reactions that are difficult to tolerate, such as nausea, vomiting, rash, hepatitis, etc., and the recurrence rate is high. Therefore, finding new drugs for the treatment of UC with good clinical efficacy, high safety, and low recurrence rate is a hot topic of research at home and abroad.

[0003] Naringin was first discovered in the flowers of grapefruit trees growing in Java in 1857. Studies have found that naringin has a wide range of effects, including antioxidant, neuroprotective, anti-inflammatory, anti-allergic, anti-cancer, anti-mutagenic, anti-viral, anti-ulcer, analgesic and antihypertensive. pH / enzyme dual-responsive colon-targeted drop pills have the characteristics of high bioavailability, strong drug stability, and the ability to achieve targeted drug delivery. However, there are many influencing factors in the preparation process of the drop pills. The drop distance, melting temperature of the drug solution, and the type of matrix will affect the roundness of the drop pills. In summary, the prior art generally has technical problems such as low bioavailability of naringin and poor roundness of enteric-coated drop pills, resulting in low release of the drop pills. Summary of the invention

[0004] In view of the problems existing in the above prior art, the present invention provides a naringin pH / enzyme dual-responsive colon-targeted drop pill and a preparation method thereof. The naringin pH / enzyme dual-responsive colon-targeted drop pill of the present invention is an enteric-coated drop pill with a parallel system, which can avoid the problem of incomplete drug release and low bioavailability caused by changes in pH value in the colon caused by pathological factors. It is specifically achieved by the following technology.

[0005] A naringin pH / enzyme dual-responsive colon-targeted drop pill, comprising an enteric layer coating and a pill core in a mass ratio of (5-9):(12-16);

[0006] The enteric layer coating comprises the following raw materials by weight: 20-40 parts of polyacrylic acid resin III, 10-20 parts of talc, 2-4 parts of polyethylene glycol 6000, 10-20 parts of resistant starch, and 200-400 parts of ethanol;

[0007] The pellet core comprises naringin and a matrix in a mass ratio of 1:(2-4).

[0008] At present, oral colon drug delivery systems mainly use single-regulated colon-targeted preparations. Although the preparation is relatively simple, the preparation may be affected by individual differences in patients and reduce the targeting performance. For example, under pathological conditions, the pH value in the colon will be lower than the pH value under normal conditions, which may cause the drug in the pH-responsive dosage form to be unable to be fully released and excreted from the body. Therefore, this experiment took advantage of the difference between the pH value in the colon and that in the stomach and small intestine to construct a pH / enzyme dual-responsive colon-targeted drop pill for delivering naringin. Under the action of the pH value range of the colon, the film coating layer of the drop pill gradually dissolves to release the drug. The dosage form has a dual-regulatory nature, avoiding the phenomenon of drug non-release caused by the failure of a single regulatory mechanism, improving the bioavailability of naringin, and providing a certain reference value for the pharmacological activity evaluation of naringin and its pharmaceutical research.

[0009] Furthermore, the enteric layer coating comprises the following raw materials by weight: 29-31 parts of polyacrylic acid resin III, 10-20 parts of talc, 2-4 parts of polyethylene glycol, 14-15.5 parts of resistant starch, and 200-400 parts of ethanol.

[0010] Furthermore, in the enteric layer coating, the mass fraction of polyacrylic acid resin III is 6-10%.

[0011] Furthermore, the matrix includes at least one of polyethylene glycols (such as PEG6000, PEG4000, etc.), polyvinylpyrrolidone (PVP), sodium stearate, poloxamer, polyoxyl (40) stearate or gelatin.

[0012] Furthermore, the matrix includes polyethylene glycol 4000 (PEG4000) and polyethylene glycol 6000 (PEG6000) in a mass ratio of (2-5):1.

[0013] Furthermore, the preparation method of the enteric layer coating comprises the following steps:

[0014] Add talcum powder, polyethylene glycol 6000 and resistant starch into ethanol and mix well, add polyacrylic acid resin III, mix well, and sieve to obtain a liquid enteric layer coating.

[0015] Furthermore, the preparation method of the pellet core comprises the following steps:

[0016] The matrix is ​​heated and melted, naringin is added and mixed, and the mixture is dripped into a pre-cooled condensation medium at a drop distance of 5.3-6.8 cm and a drop rate of 25-30 drops / min, condensed, solidified, and centrifuged to obtain a pellet core.

[0017] Furthermore, the melting temperature is 85-95°C.

[0018] Furthermore, the condensing medium includes any one of dimethyl silicone oil, liquid paraffin, and vegetable oil.

[0019] Furthermore, the precooling temperature is 0-10°C.

[0020] The matrix in the core of the naringin pH / enzyme dual-responsive colon-targeted drop pill of the present invention is a drug carrier of the main drug naringin, which can effectively release the drug while not affecting the stability of the drug. Polyethylene glycol 4000 and polyethylene glycol 6000 are water-soluble matrices that are widely used, but it is found in the research process that polyethylene glycol 6000 often causes patients to become dependent. The inventor has found that the matrix of the core of the pill can be formed by using polyethylene glycol 4000 and polyethylene glycol 6000 in a suitable ratio, which can not only reduce the patient's dependence on polyethylene glycol 6000, but also effectively improve the dispersibility of the drug in the colon and enhance the bioavailability of the drug.

[0021] The preparation method of the above-mentioned naringin pH / enzyme dual-responsive colon-targeted dripping pills comprises the following steps:

[0022] The pellet core is coated with a liquid enteric layer coating, and when the weight of the enteric layer coating is 20-30% of the weight of the pellet core, the pellet core is dried to obtain naringin pH / enzyme dual-responsive colon-targeted dripping pills.

[0023] The inventors of the present invention have found in their research that, in the process of preparing the pellet core, the melting temperature of the matrix, the ratio of the matrix and the temperature of the condensation medium will affect the roundness of the pellet core. When the melting temperature is low, the pellets are dropped into the condensation medium, and they condense prematurely before they can form a sphere, so they are more likely to tail and have poor roundness. When the melting temperature is high, the pellets are dropped into the condensation medium, and they will not condense immediately due to the high temperature, but will sink in the condensation medium in a molten state for a period of time. At this time, the surface tension of the condensation medium will cause the pellets to agglomerate into a round sphere. When PEG6000 is used alone, the molten medium does not disperse and flow; when PEG4000 is used alone, it is not easy to form by dripping; therefore, the appropriate ratio of PEG4000 and PEG6000 is selected, so that the dripping is easy and the pellets have good roundness. When the temperature of the condensation medium is high, the pellets are dropped into the condensation medium. Due to the high temperature of the medium, the pellets stick together before they can form a sphere, so they are more likely to stick together and have poor roundness. When the temperature of the condensation medium is low, the pellets are dropped into the condensation medium. Due to the low temperature of the medium, the pellets condense prematurely before they can form a sphere, so they are more likely to tail and have poor roundness.

[0024] In the coating process, the speed of the coating machine plays a vital role. When the coating machine is working, the coating liquid is sprayed through the nozzle onto the material carried by the uniformly rotating coating barrel. The rotation of the coating barrel enables the material to fully contact with the coating liquid. If the speed of the material barrel is too fast, the coating will be uneven, and if the speed is too slow, the coating liquid will not be easy to evaporate.

[0025] The application of the above-mentioned naringin pH / enzyme dual-responsive colon-targeted dripping pills in the treatment of ulcerative colitis.

[0026] Compared with the prior art, the present invention is beneficial in that:

[0027] 1. The present invention uses polyacrylic acid resin III, resistant starch, etc. as coating materials to obtain enteric-coated dripping pills with a parallel system, solving the problem of incomplete drug release and low bioavailability caused by changes in pH value in the colon;

[0028] 2. The present invention uses PEG6000 and PEG4000 as a mixed matrix to obtain pellets with round shape and moderate hardness;

[0029] 3. The present invention prepares naringin pH / enzyme dual-responsive colon-targeted drop pills with high drug solubility, high biological usability and good stability in the form of drop pills; by controlling the mass ratio of the matrix to naringin, the heating temperature of the drug-containing matrix and the drop distance, the formation rate of the drop pills can reach more than 90%. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The naringin pH / enzyme dual-responsive colon-targeted drop pills prepared in Example 3;

[0031] Figure 2 The response surface diagram of the response surface optimization results for the dosage of polyacrylic acid resin III and resistant starch;

[0032] Figure 3 The response surface diagram of the response surface optimization results for the dosage of polyacrylic acid resin III and coating weight gain;

[0033] Figure 4 Response surface plot of the response surface optimization results for resistant starch dosage and coating weight gain. DETAILED DESCRIPTION

[0034] In order to further illustrate the present invention, the technical solutions provided by the present invention are described in detail below in conjunction with embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0035] The present invention provides an exemplary naringin pH / enzyme dual-responsive colon-targeted dripping pill, comprising an enteric layer coating and a pill core in a mass ratio of (5-9):(12-16); wherein the enteric layer coating comprises the following raw materials in parts by weight: 20-40 parts of polyacrylic acid resin III, 10-20 parts of talc, 2-4 parts of polyethylene glycol 6000, 10-20 parts of resistant starch, and 200-400 parts of ethanol; and the pill core comprises naringin and a matrix in a mass ratio of 1:(2-4).

[0036] In some examples of the present invention, the enteric layer coating includes the following raw materials by weight: 29-31 parts of polyacrylic acid resin III, 10-20 parts of talc, 2-4 parts of polyethylene glycol 6000, 14-15.5 parts of resistant starch, and 200-400 parts of ethanol.

[0037] In some examples of the present invention, in the enteric layer coating, the mass fraction of polyacrylic acid resin III is 6-10%.

[0038] In some examples of the present invention, the matrix may include at least one of polyethylene glycols (eg, PEG6000, PEG4000, etc.), polyvinylpyrrolidone (PVP), sodium stearate, poloxamer, polyoxyl (40) stearate, or gelatin.

[0039] In some examples of the present invention, the matrix includes polyethylene glycol 4000 (PEG4000) and polyethylene glycol 6000 (PEG6000) in a mass ratio of (2-5):1.

[0040] The present invention provides an exemplary method for preparing an enteric layer coating, comprising the following steps:

[0041] Add talcum powder, polyethylene glycol 6000 and resistant starch to 95% by volume ethanol and mix well, add polyacrylic acid resin III, mix well, and sieve to obtain a liquid enteric layer coating.

[0042] The present invention also provides an exemplary method for preparing a pellet core, comprising the following steps:

[0043] The matrix is ​​heated and melted, naringin is added and mixed, and the mixture is dripped into a pre-cooled condensation medium at a drop distance of 5.3-6.8 cm and a drop rate of 25-30 drops / min, condensed, solidified, and centrifuged to obtain a pellet core.

[0044] In some examples of the present invention, the melting temperature is 85-95°C.

[0045] In some examples of the present invention, the solution is dripped into a condensation medium precooled to 0-10° C. at a dripping distance of 5.3 cm and a dripping rate of 25 drops / min.

[0046] In some examples of the present invention, the condensing medium may include any one of dimethyl silicone oil, liquid paraffin, and vegetable oil.

[0047] In the method for preparing the pellet core of the present invention, centrifugation is a conventional operation, and conventional selection of parameters can be performed in order to prepare the pellet core.

[0048] The present invention also provides an exemplary method for preparing naringin pH / enzyme dual-responsive colon-targeted drop pills, comprising the following steps:

[0049] The pellet core is coated with the liquid enteric layer coating. When the weight of the enteric layer coating is 20-30% of the weight of the pellet core (i.e., the coating weight gain is 20-30%), drying is performed to obtain naringin pH / enzyme dual-responsive colon-targeted dripping pills.

[0050] In some examples of the present invention, when the dripping pills are coated, the pill cores are placed in a high-efficiency coating machine, the coating machine speed is set to 25-40rpm, the inlet air temperature is 20-40°C, the outlet air temperature is 15-20°C, preheating is 20min, and then coating is performed. The liquid enteric layer coating is sprayed from a spray gun with an atomization pressure value of 0.10-0.15Mpa. When the coating weight gain is 20%-30%, it is taken out, placed in a blower, and dried at 20°C for 0.5h.

[0051] The technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0052] In this embodiment, the coating temperature in the preparation method of the naringin pH / enzyme dual-responsive colon-targeted drop pills includes material temperature, air inlet temperature and air outlet temperature. To facilitate subsequent animal experiments, the particle size of the naringin pH / enzyme dual-responsive colon-targeted drop pills in this specific embodiment is controlled to be 2.0 mm.

[0053] In the present invention, the formation rate of naringin pH / enzyme dual-responsive colon-targeted drop pills (X) = the number of round and smooth drop pills ÷ the total number of drop pills × 100%.

[0054] Example 1

[0055] This embodiment provides a naringin pH / enzyme dual-responsive colon-targeted dropping pill, comprising an enteric layer coating and a pill core in a mass ratio of 7:14.

[0056] The enteric layer coating comprises the following raw materials in parts by weight: 20 parts of polyacrylic acid resin III, 10 parts of talc, 2 parts of polyethylene glycol 6000, 15 parts of resistant starch, and 200 parts of 95% ethanol.

[0057] The preparation method of the enteric layer coating comprises the following steps:

[0058] S1. Add talcum powder, polyethylene glycol 6000 and resistant starch into 95% ethanol and mix well to obtain a mixed solution;

[0059] S2. Slowly add polyacrylic acid resin III to the mixed solution of step S1 and pass through an 80-mesh sieve to obtain an enteric layer coating.

[0060] The pellet core comprises naringin and a matrix in a mass ratio of 1:3, and the matrix comprises polyethylene glycol 4000 and polyethylene glycol 6000 in a mass ratio of 3:1.

[0061] The preparation method of the pellet core comprises the following steps:

[0062] The matrix was placed in a beaker, heated in a water bath at 85°C, and stirred until fully melted. Naringin was then slowly added while stirring, mixed, and loaded into a pill machine. Under the conditions of a drop distance of 5.3 cm and a drop rate of 25 drops / min, the matrix was dropped into a dimethyl silicone oil condensation medium precooled to 0°C. After condensation and solidification, pills were formed. The condensation medium was removed by centrifugation, dried, and the pill cores were obtained, which were sealed and stored.

[0063] The preparation method of the naringin pH / enzyme dual-responsive colon-targeted drop pills comprises the following steps:

[0064] The pill core is placed in a high-efficiency coating machine, the coating machine speed is set to 25 rpm, the air inlet temperature is set to 20°C, the air outlet temperature is set to 15°C, and preheating is performed for 20 minutes, and then coating is performed. The liquid enteric layer coating is sprayed from a spray gun with an atomization pressure value of 0.10 MPa. When the coating weight reaches 20% of the pill core weight, it is taken out, placed in a blower box, and dried at 20°C for 0.5 hours to obtain naringin pH / enzyme dual-responsive colon-targeted drop pills.

[0065] In this embodiment, the formation rate of naringin pH / enzyme dual-responsive colon-targeted drop pills was 53.0%.

[0066] Example 2

[0067] This embodiment provides a naringin pH / enzyme dual-responsive colon-targeted dropping pill, comprising an enteric layer coating and a pill core in a mass ratio of 7:14.

[0068] The enteric layer coating comprises the following raw materials in parts by weight: 40 parts of polyacrylic acid resin III, 20 parts of talc, 4 parts of polyethylene glycol 6000, 20 parts of resistant starch, and 400 parts of 95% ethanol.

[0069] The preparation method of the enteric layer coating comprises the following steps:

[0070] S1. Add talcum powder, polyethylene glycol 6000 and resistant starch into 95% ethanol and mix well to obtain a mixed solution;

[0071] S2. Slowly add polyacrylic acid resin III to the mixed solution of step S1 and pass through an 80-mesh sieve to obtain an enteric layer coating.

[0072] The pellet core comprises naringin and a matrix in a mass ratio of 1:3, and the matrix comprises polyethylene glycol 4000 and polyethylene glycol 6000 in a mass ratio of 3:1.

[0073] The preparation method of the pellet core comprises the following steps:

[0074] The matrix was placed in a beaker, heated in a water bath at 85°C, and stirred until fully melted. Naringin was then slowly added while stirring, mixed, and loaded into a pill machine. Under the conditions of a drop distance of 5.3 cm and a drop rate of 25 drops / min, the matrix was dropped into a dimethyl silicone oil condensation medium precooled to 0°C. After condensation and solidification, pills were formed. The condensation medium was removed by centrifugation, dried, and the pill cores were obtained, which were sealed and stored.

[0075] The preparation method of the naringin pH / enzyme dual-responsive colon-targeted drop pills comprises the following steps:

[0076] The pill core is placed in a high-efficiency coating machine, the coating machine speed is set to 25 rpm, the air inlet temperature is set to 20° C., the air outlet temperature is set to 15° C., preheated for 20 min, and then coated. The liquid enteric layer coating is sprayed from a spray gun with an atomization pressure value of 0.15 MPa. When the coating weight reaches 30% of the pill core weight, it is taken out, placed in a blower box, and dried at 20° C. for 0.5 h to obtain naringin pH / enzyme dual-responsive colon-targeted drop pills.

[0077] In this embodiment, the formation rate of naringin pH / enzyme dual-responsive colon-targeted drop pills was 62.7%.

[0078] Example 3

[0079] This embodiment provides a naringin pH / enzyme dual-responsive colon-targeted dropping pill, comprising an enteric layer coating and a pill core in a mass ratio of 7:14.

[0080] The enteric layer coating comprises the following raw materials in parts by weight: 30 parts of polyacrylic acid resin III, 15 parts of talc, 3 parts of polyethylene glycol 6000, 15 parts of resistant starch, and 300 parts of 95% ethanol.

[0081] The preparation method of the enteric layer coating comprises the following steps:

[0082] S1. Add talcum powder, polyethylene glycol 6000 and resistant starch into 95% ethanol and mix well to obtain a mixed solution;

[0083] S2. Slowly add polyacrylic acid resin III to the mixed solution of step S1 and pass through an 80-mesh sieve to obtain an enteric layer coating.

[0084] The pellet core comprises naringin and a matrix in a mass ratio of 1:3, and the matrix comprises polyethylene glycol 4000 and polyethylene glycol 6000 in a mass ratio of 3:1.

[0085] The preparation method of the pellet core comprises the following steps:

[0086] The matrix was placed in a beaker, heated in a water bath at 90°C, and stirred until fully melted. Naringin was then slowly added while stirring, mixed, and loaded into a pill machine. Under the conditions of a drop distance of 6 cm and a drop rate of 27 drops / min, the matrix was dropped into a dimethyl silicone oil condensation medium precooled to 5°C. After condensation and solidification, pills were formed. The condensation medium was removed by centrifugation, dried, and the pill cores were obtained, which were sealed and stored.

[0087] The preparation method of the naringin pH / enzyme dual-responsive colon-targeted drop pills comprises the following steps:

[0088] The pellet core is placed in a high-efficiency coating machine, the coating machine speed is set to 30 rpm, the air inlet temperature is 30° C., the air outlet temperature is 17° C., preheated for 20 min, and then coated. The liquid enteric layer coating is sprayed from a spray gun with an atomization pressure value of 0.13 MPa. When the coating weight reaches 25% of the pellet core weight, it is taken out and placed in a blower box, and dried at 20° C. for 0.5 h to obtain naringin pH / enzyme dual-responsive colon-targeted drop pills. The prepared drop pill product is as follows Figure 1 shown.

[0089] In this embodiment, the formation rate of naringin pH / enzyme dual-responsive colon-targeted drop pills was 90.2%.

[0090] Example 4

[0091] This embodiment is basically the same as embodiment 3, except that the amount of polyacrylic acid resin III in the enteric layer coating is 20 parts.

[0092] That is, compared with Example 3, the amount of polyacrylic acid resin III was reduced in this comparative example.

[0093] In this embodiment, the formation rate of naringin pH / enzyme dual-responsive colon-targeted drop pills was 73.6%.

[0094] Example 5

[0095] This embodiment is basically the same as embodiment 3, except that the amount of polyacrylic acid resin III in the enteric layer coating is 40 parts.

[0096] That is, compared with Example 3, the amount of polyacrylic acid resin III is increased in this comparative example.

[0097] In this embodiment, the formation rate of naringin pH / enzyme dual-responsive colon-targeted drop pills was 82.4%.

[0098] Example 6

[0099] This embodiment is basically the same as embodiment 3, except that the amount of resistant starch in the enteric layer coating is 10 parts.

[0100] That is, compared with Example 3, the amount of resistant starch used in this comparative example was reduced.

[0101] In this embodiment, the formation rate of naringin pH / enzyme dual-responsive colon-targeted drop pills was 85.4%.

[0102] Example 7

[0103] This embodiment is basically the same as embodiment 3, except that the amount of resistant starch in the enteric layer coating is 20 parts.

[0104] That is, compared with Example 3, the amount of resistant starch was increased in this comparative example.

[0105] In this embodiment, the formation rate of naringin pH / enzyme dual-responsive colon-targeted drop pills was 83.2%.

[0106] Example 8

[0107] This example is basically the same as Example 3, except that in the preparation method of naringin pH / enzyme dual-responsive colon-targeted dropping pills, the weight of the enteric layer coating is 20% of the weight of the pill core.

[0108] That is, compared with Example 3, the coating weight gain of the naringin pH / enzyme dual-responsive colon-targeted drop pills in this comparative example during the coating process was 20%.

[0109] In this embodiment, the formation rate of naringin pH / enzyme dual-responsive colon-targeted drop pills was 87.3%.

[0110] Example 9

[0111] This example is basically the same as Example 3, except that in the preparation method of naringin pH / enzyme dual-responsive colon-targeted dropping pills, the weight of the enteric layer coating is 30% of the weight of the pill core.

[0112] That is, compared with Example 3, the coating weight gain of the naringin pH / enzyme dual-responsive colon-targeted drop pills in this comparative example during the coating process was 30%.

[0113] In this embodiment, the formation rate of naringin pH / enzyme dual-responsive colon-targeted drop pills was 89.5%.

[0114] Test Example 1

[0115] Poor roundness of the pills will affect the thickness uniformity of the coating, resulting in sudden release or hysteresis of the drug during the release process, resulting in a decrease in the drug concentration when the drug reaches the colon and a decrease in drug efficacy. The naringin pH / enzyme dual-responsive colon-targeted pills prepared in Examples 1-9 were tested for pill shape and hardness, and the hardness (hand-pressing test) and roundness of the pills were used as indicators and evaluated using a 5-point scoring system. The higher the score, the better the comprehensive index. The scoring criteria are shown in Table 1, and the test results are shown in Table 2.

[0116] Table 1 Rating criteria for hardness and roundness of pellets

[0117]

[0118] Table 2 Results of hardness and roundness of pills in Examples 1-9

[0119]

[0120] As can be seen from Table 2, the hardness and roundness of the pills of the present invention are both above 3 points, and the hardness and roundness of the pills in Example 3 can both reach the highest score. This shows that the naringin pH / enzyme dual-responsive colon-targeted pills prepared using the raw material formula and preparation method of the present invention have good hardness and roundness.

[0121] Test Example 2

[0122] The inventors used a single factor experiment to determine the influencing factors and levels of the release of naringin pH / enzyme dual-responsive colon-targeted drop pills. Among them, the factors are the amount of polyacrylic acid resin III (parts by weight), the amount of resistant starch (parts by weight), and the coating weight gain (%); the other raw materials and amounts of the drop pills are the same as those in Example 3. The specific steps are as follows:

[0123] (1) Using the Box-Behnken model experimental design, factors A, B and C were used as response variables, and the response value was the drug formation rate. Response surface analysis was performed. The response surface diagram of the response surface optimization result is shown in the figure below. Figure 2-4 As shown. Among them, factor A is the amount of polyacrylic acid resin III (parts by weight). Factor B is the amount of resistant starch (parts by weight). Factor C is the coating weight gain (%).

[0124] Among them, factor A takes 20, 30, and 40 values, corresponding to levels -1, 0, and 1 respectively; factor B takes 10, 15, and 20 values, corresponding to levels -1, 0, and 1 respectively; factor C takes 20%, 25%, and 30%, corresponding to levels -1, 0, and 1 respectively. The factor level table is shown in Table 3.

[0125] Table 3 Box-Behnken test factor level table

[0126]

[0127] Depend on Figure 2 It can be seen that the cumulative release rate of naringin pH / enzyme dual-responsive colon-targeted pellets first increased and then decreased with the increase of polyacrylic acid resin III content. Figure 3 It can be seen that the cumulative release rate of naringin pH / enzyme dual-responsive colon-targeted pellets first increases and then decreases with the increase of resistant starch content. Figure 4 It can be seen that the cumulative release of naringin pH / enzyme dual-responsive colon-targeted pellets decreases with the increase of coating weight, which is consistent with the results of variance analysis.

[0128] (2) The Box-Behnken model test in Design-Expert.11.1.0.1 obtained the quadratic polynomial equations of the cumulative release rate (X) of naringin pH / enzyme dual-responsive colon-targeted drop pills by the above three factors: factor A, factor B and factor C are as follows:

[0129] X=82.20-1.92A-10.19B-2.36C+10.55AB-11.86AC-4.53BC-26.91A 2 -7.94B 2 +0.2200C 2 (Formula I)

[0130] In the above formula I, A represents the amount of polyacrylic acid resin III (parts by weight), B represents the amount of resistant starch (parts by weight), and C represents the coating weight gain (%).

[0131] The Box-Behnken test design and results are shown in Table 4. The response surface regression analysis model variance analysis is shown in Table 5.

[0132] Table 4 Box-Behnken test design and results

[0133]

[0134] Table 5 Analysis of variance of response surface regression analysis model

[0135]

[0136] As shown in Table 5, the regression model P < 0.05 has statistical significance, indicating that the model has a good fit and can reflect the influence of the three factors on the cumulative release rate of the drop pill (X). 2 , B 2 The cumulative release rate of naringin pH / enzyme dual-responsive colon-targeted dripping pills (X) was significantly affected (P<0.05). This shows that the relationship between the factors and the response value is not a simple linear relationship, which has a certain statistical significance.

[0137] (3) Determine the further ranges of the three factors A, B, and C: Determine the further range of A as 29.21-31.04 parts; the further range of B as 14.2-15.5 parts; the further range of C as 25.02-25.63%.

[0138] That is, in the raw materials of the naringin pH / enzyme dual-responsive colon-targeted dropping pills of the present invention, the weight parts of polyacrylic acid resin III are 29.21-31.04 parts, and the weight parts of resistant starch are 14.2-15.5 parts; at the same time, in the preparation method of the naringin pH / enzyme dual-responsive colon-targeted dropping pills, when the coating weight gain is 25.02-25.63%, the release degree of the naringin pH / enzyme dual-responsive colon-targeted dropping pills is excellent.

[0139] The present invention prepares naringin into pH / enzyme dual-responsive colon-targeted drop pills, and obtains naringin pH / enzyme dual-responsive colon-targeted drop pills with good drug solubility, high biological use, and good stability. The inventors also conducted a large number of experiments and found that compared with Example 3, when PEG40000 was used alone as a matrix, the pill shape was better but the hardness was poor; when PEG6000 was used alone as a matrix, the drop pills were not easy to form, and the obtained drop pills were not round.

[0140] The above specific embodiments describe the implementation of the present invention in detail, but the present invention is not limited to the specific details in the above embodiments. Within the scope of the claims and technical concept of the present invention, the technical solution of the present invention can be modified and changed in many simple ways, and these simple modifications all belong to the protection scope of the present invention.

Claims

1. A naringin pH / enzyme dual-responsive colon-targeted dripping pill, characterized in that: It includes an enteric layer coating and a pellet core in a mass ratio of (5-9):(12-16); The enteric layer coating comprises the following raw materials by weight: 20-40 parts of polyacrylic acid resin III, 10-20 parts of talc, 2-4 parts of polyethylene glycol, 10-20 parts of resistant starch, and 200-400 parts of ethanol; The pellet core comprises naringin and a matrix in a mass ratio of 1:(2-4).

2. The naringin pH / enzyme dual-responsive colon-targeted dripping pill according to claim 1, characterized in that: The enteric layer coating comprises the following raw materials by weight: 29-31 parts of polyacrylic acid resin III, 10-20 parts of talc, 2-4 parts of polyethylene glycol 6000, 14-15.5 parts of resistant starch, and 200-400 parts of ethanol.

3. The naringin pH / enzyme dual-responsive colon-targeted dripping pill according to claim 2, characterized in that: In the enteric layer coating, the mass fraction of polyacrylic acid resin III is 6-10%.

4. The naringin pH / enzyme dual-responsive colon-targeted dripping pill according to claim 1, characterized in that: The matrix includes polyethylene glycol 4000 and polyethylene glycol 6000 in a mass ratio of (2-5):

1.

5. The naringin pH / enzyme dual-responsive colon-targeted dripping pill according to claim 1, characterized in that: The preparation method of the enteric layer coating comprises the following steps: Add talcum powder, polyethylene glycol 6000 and resistant starch to ethanol and mix well, add polyacrylic acid resin III, mix well, sieve, and take the filtrate to obtain the enteric layer coating.

6. The naringin pH / enzyme dual-responsive colon-targeted dripping pill according to claim 1, characterized in that: The preparation method of the pellet core comprises the following steps: The matrix is ​​heated and melted, naringin is added and mixed, and the mixture is dripped into a pre-cooled condensation medium at a drop distance of 5.3-6.8 cm and a drop rate of 25-30 drops / min. The mixture is condensed and solidified, and centrifuged to obtain a pellet core.

7. The naringin pH / enzyme dual-responsive colon-targeted dripping pill according to claim 6, characterized in that: The condensing medium includes any one of dimethyl silicone oil, liquid paraffin, and vegetable oil.

8. The method for preparing the naringin pH / enzyme dual-responsive colon-targeted dripping pills according to any one of claims 1 to 7, characterized in that: The following steps are involved: The enteric layer coating is used to coat the pill core. When the weight of the enteric layer coating is 20-30% of the weight of the pill core, the pill core is dried to obtain naringin pH / enzyme dual-responsive colon-targeted dripping pills.

9. The method for preparing the naringin pH / enzyme dual-responsive colon-targeted dropping pills according to claim 8, characterized in that: The weight of the enteric layer coating is 25-25.7% of the weight of the pellet core.

10. Use of the naringin pH / enzyme dual-responsive colon-targeted dripping pills according to any one of claims 1 to 7 in the treatment of ulcerative colitis.

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