Efficiently-dissolved erythromycin cyclic ester capsule and preparation method thereof

Abstract

The invention provides an efficiently-dissolved erythromycin cyclic ester capsule and a preparation method thereof. The erythromycin cyclic ester capsule is prepared from the following raw materials in parts by mass: erythromycin cyclic ester nanocrystal freeze-dried powder, lactose, carboxymethyl starch sodium, lauryl sodium sulfate and magnesium stearate. The preparation process of the erythromycin cyclamate nanocrystal freeze-dried powder comprises the following steps: adding erythromycin cyclamate into an aqueous solution of polyethylene glycol 1000 vitamin E succinate and poloxamer 188, stirring, homogenizing to obtain an erythromycin cyclamate nanosuspension, adding glycerol into the erythromycin cyclamate nanosuspension, dissolving, pre-freezing, and freeze-drying to obtain the erythromycin cyclamate nanocrystal freeze-dried powder. The erythromycin cyclic ester capsule is simple in preparation process, high in drug stability, high in dissolution rate and suitable for large-scale production and application, and the method can improve the drug utilization rate.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a high-efficiency dissolving cyclic erythromycin capsule and a preparation method thereof. Background Art

[0002] Cyclic erythromycin is a new type of erythromycin derivative. + It has strong antibacterial activity against anaerobic bacteria and is mostly used in clinical practice for infections induced by sensitive bacteria. However, its development and application are affected by solubility, bioavailability, and distribution of the drug in the body, which affects its expanded application. Cyclic erythromycin is a low-solubility, low-permeability drug, a white or off-white crystalline powder, easily soluble in methanol and propanol, and almost insoluble in water. Under conditions of high temperature, high humidity, and light, the stability of cyclic erythromycin is affected to a certain extent, and as a macrolide product, it is unstable in acid and easily destroyed in gastric acid.

[0003] Polyethylene glycol 1000 vitamin E succinate (TPGS) is a commonly used excipient in drug delivery systems, mainly used to improve the solubility, bioavailability and stability of drugs. Polyethylene glycol 1000 vitamin E succinate works mainly in the following ways: Increase drug solubility: TPGS has good water solubility and can form complexes with hydrophobic drugs, thereby increasing the solubility of drugs in water. This makes the drug more easily absorbed by the human body and improves the bioavailability of the drug. Protect drugs from enzymatic degradation: It can wrap on the surface of the drug to form a protective film to prevent the drug from being degraded by enzymes in the body. This helps to prolong the drug's action time and improve the efficacy of the drug. TPGS has an antioxidant effect, which can protect drugs from oxidative damage, and can also inhibit the interaction between drugs and other substances, reducing the decomposition and degradation of drugs. Improve the pharmacokinetic properties of drugs: It can improve the absorption of drugs and reduce the fluctuation of plasma concentrations of drugs, thereby improving the pharmacokinetic properties of drugs. Reduce the side effects of drugs: It can reduce the accumulation of drugs in the body and reduce the toxicity and side effects of drugs.

[0004] At present, the film coating of the commercially available erythromycin film-coated tablets will dissolve in a few minutes under the gastric acid environment, which cannot well solve the problem that the drug is easily destroyed in the gastric acid environment, and is easy to cause gastrointestinal dysfunction: such as nausea, vomiting, diarrhea and other adverse reactions, which easily cause patients to have a resistance to taking the drug, which is not conducive to the patient's medication. In addition, the production process of the commercially available erythromycin tablets is complicated, time-consuming, costly, and not suitable for large-scale production. At the same time, the commercially available erythromycin capsules have the disadvantages of poor capsule sealing, uneven particle distribution, poor drug stability, etc. For this reason, the present invention uses raw material polyethylene glycol 1000 vitamin E succinate to prepare erythromycin nanocrystalline freeze-dried powder, and provides an efficient dissolution erythromycin capsule and a preparation method thereof. Summary of the invention

[0005] In view of this, in order to prevent erythromycin from being destroyed in the acidic environment of the stomach, reduce the acidic stimulation to the stomach, better exert the effect of the drug, facilitate patients to take the drug, and enhance the stability and dissolution rate of the drug, the present invention provides a erythromycin capsule, which is dissolved and absorbed in the small intestine, dissolves and quickly releases the active component, reduces gastric stimulation, and improves the bioavailability and stability of erythromycin.

[0006] The technical solution of the present invention is achieved in this way:

[0007] A method for preparing a highly efficient dissolving erythromycin cyclohexyl capsule comprises the following raw materials in parts by weight: 70-80 parts of erythromycin cyclohexyl nanocrystalline freeze-dried powder, 5-7 parts of lactose, 3-5 parts of sodium carboxymethyl starch, 3-5 parts of sodium lauryl sulfate, and 2-4 parts of magnesium stearate, and comprises the following steps:

[0008] S1. Divide the erythromycin cyclic ester nanocrystalline freeze-dried powder into two parts to obtain erythromycin cyclic ester nanocrystalline freeze-dried powder I and erythromycin cyclic ester nanocrystalline freeze-dried powder II;

[0009] S2, centrifugally crushing lactose, sodium carboxymethyl starch, sodium lauryl sulfate, and magnesium stearate, respectively, and sieving to obtain an auxiliary material mixture;

[0010] S3, mixing the erythromycin cyclic ester nanocrystal freeze-dried powder I and the auxiliary material mixture, stirring to obtain a primary mixed drug;

[0011] S4. Mix the erythromycin cyclic ester nanocrystalline freeze-dried powder II and the primary mixed drug, stir, perform high shear wet granulation, dry, and use capsule filling and sealing to prepare erythromycin cyclic ester capsules.

[0012] The preparation process of erythromycin cyclic ester nanocrystalline freeze-dried powder includes:

[0013] S1. Weigh erythromycin cycloheximide, add it to the aqueous solution of polyethylene glycol 1000 vitamin E succinate and poloxamer 188 to obtain a mixed solution I;

[0014] S2. Stir and homogenize the mixed solution I to obtain a cyclic erythromycin nanosuspension.

[0015] S3. Add glycerol to the erythromycin cyclic ester nanosuspension, stir to dissolve, pre-freeze, and freeze-dry to obtain erythromycin cyclic ester nanocrystalline freeze-dried powder.

[0016] Furthermore, S1, the volume fractions of polyethylene glycol 1000 vitamin E succinate and poloxamer 188 are 0.4-0.6% and 0.2-0.3% respectively, and the mass volume ratio of erythromycin cyclic ester, polyethylene glycol 1000 vitamin E succinate, poloxamer 188 and water is (5-8) g: (0.25-0.35) g: (0.1-0.2) g: (45-50) mL.

[0017] Further, S2, the stirring speed is 5500-6000 rpm, the time is 20-35 min, the temperature is 10-30°C, the homogenization is 1-2 times, and the pressure is 800-850 bar.

[0018] Further, S3, the volume fraction of glycerol is 2-4%, the pre-freezing, the pre-freezing temperature is -80 to -85°C, the pre-freezing time is 30-36h, and the pre-freezing and freeze-drying are performed, the freezing temperature is -90 to -100°C, and the drying time is 30-35h.

[0019] Furthermore, S1, the mass ratio of the erythromycin cyclic ester nanocrystalline freeze-dried powder I and the erythromycin cyclic ester nanocrystalline freeze-dried powder II is (5-10):(65-70).

[0020] Furthermore, S2, the centrifugal crushing has a centrifugal speed of 800-1000 rpm and a crushing particle size of 120-140 microns.

[0021] Further, S3, S4, the mixing, the barrel speed is 12-15rpm, the blade speed is 30-35rpm, the mixing time is 5-8min, the stirring is magnetic stirring, the speed is 300-400rpm, and the time is 20-30min.

[0022] Further, S4, the capsule is filled and sealed, the viscosity of the coating liquid is 135-140 mPa·s, the sealing speed is 65-70 r / min, the number of sealing is 2 times, and after sealing, it is placed at a temperature of 10-25° C. and a relative humidity of 30-40% and dried for 3.5-4.5 hours.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The raw materials of the invention, erythromycin nanocrystal freeze-dried powder, lactose, sodium carboxymethyl starch, sodium lauryl sulfate and magnesium stearate are compounded to increase the solubility and recovery rate of the active ingredient erythromycin, and improve the uniformity of the medicine. The capsule sealing technology is adopted to avoid the deterioration of the medicine in a humid environment, and the stability of the medicine is increased. At the same time, the erythromycin nanocrystal freeze-dried powder adopts erythromycin to drip polyethylene glycol 1000 vitamin E succinate aqueous solution and poloxamer 188 aqueous solution, and is stirred and dissolved with glycerol, and is pre-frozen, frozen and dried. The erythromycin nanocrystal freeze-dried powder prepared by the operation steps has a high dissolution rate, and is taken with capsules to avoid the stimulation of the medicine to the intestinal tract, which is beneficial to the absorption of the medicine. DETAILED DESCRIPTION

[0025] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0026] Unless otherwise specified, the experimental methods used in the examples of the present invention are all conventional methods, and the reagents used in the examples are all available from commercial sources.

[0027] Polyethylene glycol 1000 vitamin E succinate, chemical name: (3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-ol) polyethylene glycol succinate; purchased from Luofu Pharmaceutical Technology (Shanghai) Co., Ltd., purity content: >99%; grade specification: Level 1; implementation standard: pharmaceutical grade.

[0028] The chemical formula of Poloxamer 188 is HO·(C2H4O) m ·(C3H6O)n·H, average molecular weight: 7700-9300, purity>99%; implementation standard: pharmaceutical grade; manufacturer: Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.

[0029] Recovery rate % = actual measured amount / theoretical amount × 100%

[0030] Dissolution % = (sample absorbance × reference substance amount × number of times) / (reference absorbance × average tablet weight) × 100% Preparation Example 1

[0031] Preparation steps of erythromycin cyclic ester nanocrystal freeze-dried powder:

[0032] Step (1) Weigh erythromycin cyclohexetine, add 0.4% polyethylene glycol 1000 vitamin E succinate aqueous solution and 0.2% poloxamer 188 aqueous solution by volume, wherein the mass volume ratio of erythromycin cyclohexetine, polyethylene glycol 1000 vitamin E succinate, poloxamer 188 and water is 5g:0.25g:0.1g:45mL, to obtain a mixed solution I;

[0033] Step (2) Stirring and homogenizing the mixed solution I at a stirring speed of 5500 rpm, a time of 20 min, a temperature of 10° C., a homogenization number of 18 times, and a pressure of 800 bar to obtain a cyclic erythromycin nanosuspension.

[0034] Step (3) adding 2% glycerol by volume to the erythromycin cyclohexetine nanosuspension, stirring to dissolve, pre-freezing and freeze-drying, the pre-freezing temperature is -80°C and the pre-freezing time is 30 hours, and freeze-drying after pre-freezing, the freezing temperature is -90°C and the drying time is 30 hours, so as to obtain erythromycin cyclohexetine nanocrystalline freeze-dried powder.

[0035] Preparation Example 2

[0036] Preparation steps of erythromycin cyclic ester nanocrystal freeze-dried powder:

[0037] Step (1) Weigh erythromycin cyclohexetine, add 0.6% polyethylene glycol 1000 vitamin E succinate aqueous solution and 0.3% poloxamer 188 aqueous solution by volume, wherein the mass volume ratio of erythromycin cyclohexetine, polyethylene glycol 1000 vitamin E succinate, poloxamer 188 and water is 8g:0.35g:0.1g:50mL, to obtain a mixed solution I;

[0038] Step (2) Stirring and homogenizing the mixed solution I at a stirring speed of 6000 rpm, a time of 35 min, a temperature of 30° C., a homogenization number of 20 times, and a pressure of 850 bar to obtain a cyclic erythromycin nanosuspension.

[0039] Step (3) adding 4% glycerol by volume to the erythromycin cyclic ester nanosuspension, stirring to dissolve, pre-freezing and freeze-drying, the pre-freezing temperature is -85°C and the pre-freezing time is 26 hours, and freeze-drying after pre-freezing, the freezing temperature is -100°C, and the drying time is 35 hours, so as to obtain erythromycin cyclic ester nanocrystalline freeze-dried powder.

[0040] Preparation Example 3

[0041] Preparation steps of erythromycin cyclic ester nanocrystal freeze-dried powder:

[0042] Step (1) Weigh erythromycin cyclohexetine, add 0.5% polyethylene glycol 1000 vitamin E succinate aqueous solution and 0.25% poloxamer 188 aqueous solution by volume, wherein the mass volume ratio of erythromycin cyclohexetine, polyethylene glycol 1000 vitamin E succinate, poloxamer 188 and water is 6g:0.3g:0.15g:48mL, to obtain a mixed solution I;

[0043] Step (2) Stirring and homogenizing the mixed solution I at a stirring speed of 5800 rpm, a time of 30 min, a temperature of 20° C., a homogenization number of 19 times, and a pressure of 830 bar to obtain a cyclic erythromycin nanosuspension.

[0044] Step (3) adding 3% glycerol by volume to the erythromycin cyclic ester nanosuspension, stirring to dissolve, pre-freezing and freeze-drying, the pre-freezing temperature is -83°C and the pre-freezing time is 35h, and freeze-drying after pre-freezing, the freezing temperature is -95°C, and the drying time is 33h, so as to obtain erythromycin cyclic ester nanocrystalline freeze-dried powder.

[0045] Example 1

[0046] A method for preparing an efficient dissolving erythromycin cyclic ester capsule, characterized in that it comprises the following raw materials in parts by weight: 70 parts of erythromycin cyclic ester nanocrystalline freeze-dried powder, 5 parts of lactose, 3 parts of sodium carboxymethyl starch, 3 parts of sodium lauryl sulfate, and 2 parts of magnesium stearate, and comprises the following steps:

[0047] Step (1) dividing the erythromycin cycloester nanocrystalline freeze-dried powder into two parts, erythromycin cycloester nanocrystalline freeze-dried powder I and erythromycin cycloester nanocrystalline freeze-dried powder II, with a mass ratio of 5:67;

[0048] Step (2) centrifugally crushing lactose, sodium carboxymethyl starch, sodium lauryl sulfate, and magnesium stearate, wherein the centrifugal speed is 800 rpm, the crushing particle size is 120 microns, and sieving to obtain an auxiliary material mixture;

[0049] Step (3) mixing the erythromycin cyclic ester nanocrystalline freeze-dried powder I and the auxiliary material mixture, during mixing, the barrel speed is 12 rpm, the blade speed is 30 rpm, the mixing time is 5 min, and after mixing, magnetic stirring is performed at a stirring speed of 300 rpm for 20 min to obtain a primary mixed drug;

[0050] Step (4) mixing the erythromycin cyclic ester nanocrystalline freeze-dried powder II and the primary mixed drug, stirring, high shear wet granulation, drying, and capsule filling and sealing. The viscosity of the coating solution during sealing is 135 mPa·s, the sealing speed is 65 r / min, the number of sealings is 2 times, and after sealing, the temperature is 10° C. and the relative humidity is 30% for drying. The drying time is 3.5 hours to prepare erythromycin cyclic ester capsules.

[0051] The erythromycin cyclic ester nanocrystalline freeze-dried powder was prepared according to the method of Preparation Example 3.

[0052] Example 2

[0053] A method for preparing an efficient dissolving erythromycin cyclic ester capsule, characterized in that it comprises the following raw materials in parts by weight: 80 parts of erythromycin cyclic ester nanocrystalline freeze-dried powder, 7 parts of lactose, 5 parts of sodium carboxymethyl starch, 5 parts of sodium lauryl sulfate, and 4 parts of magnesium stearate, and comprises the following steps:

[0054] Step (1) dividing the erythromycin cycloester nanocrystalline freeze-dried powder into two parts, erythromycin cycloester nanocrystalline freeze-dried powder I and erythromycin cycloester nanocrystalline freeze-dried powder II, with a mass ratio of 10:70;

[0055] Step (2) centrifugally crushing lactose, sodium carboxymethyl starch, sodium lauryl sulfate, and magnesium stearate, wherein the centrifugal speed is 1000 rpm, the crushing particle size is 140 microns, and sieving to obtain an auxiliary material mixture;

[0056] Step (3) mixing the erythromycin cyclic ester nanocrystalline freeze-dried powder I and the auxiliary material mixture, the barrel speed during mixing is 15 rpm, the blade speed is 35 rpm, the mixing time is 8 min, and after mixing, magnetic stirring is performed at a stirring speed of 400 rpm for 30 min to obtain a primary mixed drug;

[0057] Step (4) mixing the erythromycin cyclic ester nanocrystalline freeze-dried powder II and the primary mixed drug, stirring, high shear wet granulation, drying, and capsule filling and sealing. The viscosity of the coating solution during sealing is 140 mPa·s, the sealing speed is 70 r / min, the number of sealings is 2 times, and after sealing, the mixture is placed at a temperature of 25° C. and a relative humidity of 40% for drying for a drying time of 4.5 hours to prepare erythromycin cyclic ester capsules.

[0058] The erythromycin cyclic ester nanocrystalline freeze-dried powder was prepared according to the method of Preparation Example 2.

[0059] Example 3

[0060] A method for preparing an efficient dissolving erythromycin cyclic ester capsule, characterized in that it comprises the following raw materials in parts by weight: 75 parts of erythromycin cyclic ester nanocrystalline freeze-dried powder, 6 parts of lactose, 4 parts of sodium carboxymethyl starch, 4 parts of sodium lauryl sulfate, and 3 parts of magnesium stearate, and comprises the following steps:

[0061] Step (1) dividing the erythromycin cyclohexetate nanocrystalline freeze-dried powder into two parts, erythromycin cyclohexetate nanocrystalline freeze-dried powder I and erythromycin cyclohexetate nanocrystalline freeze-dried powder II, with a mass ratio of 7:68;

[0062] Step (2) centrifugally crushing lactose, sodium carboxymethyl starch, sodium lauryl sulfate, and magnesium stearate, wherein the centrifugal speed is 900 rpm, the crushing particle size is 130 microns, and sieving to obtain an auxiliary material mixture;

[0063] Step (3) mixing the erythromycin cyclic ester nanocrystalline freeze-dried powder I and the auxiliary material mixture, the barrel speed during mixing is 13 rpm, the blade speed is 34 rpm, the mixing time is 6 min, and after mixing, magnetic stirring is performed at a stirring speed of 350 rpm for 25 min to obtain a primary mixed drug;

[0064] Step (4) mixing the erythromycin cyclic ester nanocrystalline freeze-dried powder II and the primary mixed drug, stirring, high shear wet granulation, drying, and capsule filling and sealing. The viscosity of the coating solution during sealing is 135 mPa·s, the sealing speed is 65 r / min, the number of sealings is 2 times, and after sealing, the temperature is placed at 20° C. and the relative humidity is 35% for drying. The drying time is 4 hours to prepare erythromycin cyclic ester capsules.

[0065] The erythromycin cycloheximide nanocrystalline freeze-dried powder was prepared according to the method of Preparation Example 1.

[0066] Comparative Example 1

[0067] The main difference between Comparative Example 1 and Example 3 is that the erythromycin cyclohexetate nanocrystalline freeze-dried powder is replaced with erythromycin cyclohexetate, and the contents, proportions and preparation methods of other raw materials remain unchanged.

[0068] Comparative Example 2

[0069] The main difference between Comparative Example 2 and Example 3 is that the erythromycin cyclohexetate nanocrystalline freeze-dried powder is divided into two parts and mixed separately instead of being mixed at one time, and the contents, proportions and preparation methods of other raw materials remain unchanged.

[0070] A method for preparing an efficient dissolving erythromycin cyclic ester capsule, characterized in that it comprises the following raw materials in parts by weight: 75 parts of erythromycin cyclic ester nanocrystalline freeze-dried powder, 6 parts of lactose, 4 parts of sodium carboxymethyl starch, 4 parts of sodium lauryl sulfate, and 3 parts of magnesium stearate, and comprises the following steps:

[0071] Step (1) centrifugally crushing lactose, sodium carboxymethyl starch, sodium lauryl sulfate and magnesium stearate respectively, wherein the centrifugal speed is 900 rpm, the crushing particle size is 130 microns, and sieving to obtain an auxiliary material mixture;

[0072] Step (2) mixing the erythromycin cyclic ester nanocrystalline freeze-dried powder and the auxiliary material mixture, during mixing, the barrel speed is 13 rpm, the blade speed is 34 rpm, the mixing time is 6 min, after mixing, magnetic stirring is performed, the stirring speed is 350 rpm, the time is 25 min, after stirring, high shear wet granulation is performed, drying is performed, capsule filling and sealing are performed, during sealing, the viscosity of the coating liquid is 135 mPa·s, the sealing speed is 65 r / min, the sealing times are 2 times, after sealing, the temperature is placed at 20° C. and the relative humidity is 35% for drying, and the drying time is 4 hours to prepare erythromycin cyclic ester capsules.

[0073] The erythromycin cycloheximide nanocrystalline freeze-dried powder was prepared according to the method of Preparation Example 1.

[0074] Comparative Example 3

[0075] The main difference between Comparative Example 4 and Example 3 is that Poloxamer 188 is removed from the method for preparing erythromycin cyclic ester nanocrystalline freeze-dried powder in Preparation Example 1 in Example 3, and the contents, proportions and preparation methods of other raw materials remain unchanged.

[0076] Comparative Example 4

[0077] The main difference between Comparative Example 4 and Example 3 is that the mass volume ratio of erythromycin, polyethylene glycol 1000 vitamin E succinate, poloxamer 188 and water in the method for preparing erythromycin nanocrystalline freeze-dried powder in Preparation Example 1 in Example 3 is replaced with 14g:0.1g:0.1g:45mL. The content, ratio and preparation method of other raw materials remain unchanged.

[0078] Comparative Example 5

[0079] The main difference between Comparative Example 5 and Example 3 is that the glycerol addition and pre-freezing steps are removed from Preparation Example 1 in Example 3. The other raw material contents, proportions and preparation methods remain unchanged.

[0080] Positive Control

[0081] Commercially available cyclic erythromycin capsules were used, and the manufacturer was Chongqing Saiwei Pharmaceutical Co., Ltd.

[0082] test

[0083] The dissolution determination method refers to the 2020 edition of the Chinese Pharmacopoeia. First, 900 ml of hydrochloric acid solution with a volume fraction of 1.5% is used as the dissolution medium, followed by adjusting the pH value to 6.8 with phosphate buffer, and the rotation speed is 100 revolutions per minute. After 2 hours, 2 ml of the solution is taken after 5 minutes, 20 minutes, 35 minutes, and 45 minutes, respectively, filtered, and immediately supplemented with the same temperature and the same volume of the above-mentioned phosphate buffer. Take another standard as the reference solution. High performance liquid chromatography was used for determination, using octadecylsilane bonded silica gel as the filler, phosphate solution-acetonitrile as the mobile phase, and the detection wavelength was 215 nm. Accurately measure 100 μL of the test solution and the reference solution, respectively, inject them into the liquid chromatograph, record and calculate the dissolution amount at each time point, and the calculation results are shown in Table 1.

[0084] Table 1

[0085]

[0086]

[0087] A rat test was used to detect the recovery rate of the drug in rats. The cyclic erythromycin capsules prepared in Examples 1-3 and Comparative Examples 1-5 and the positive control cyclic erythromycin capsules were administered to rats. Healthy rats weighing about 300g were selected and randomly divided into 9 groups, 3 rats in each group, fasted for 12h before administration, and had free access to water. After taking 30mg cyclic erythromycin capsules, 250μL of blood was collected from the eye sockets at 0.1, 0.3, 0.5, 1, 3, 5, and 8h after administration, and centrifuged at 3500r / min for 15min. 100μL of blood sample was accurately drawn into a centrifuge tube and stored at -15℃. Take 100 μL of plasma, add it to a centrifuge tube, add the internal standard working solution and 100 ng / mL ROC methanol solution, vortex mix, centrifuge, take the supernatant to a centrifuge tube, blow dry with nitrogen, reconstitute with 100 μL of methanol, vortex mix, centrifuge, take 5 μL of the supernatant, inject it to determine the content of erythromycin in plasma, and the determination results at 3h and 8h are shown in Table 2.

[0088] The rat plasma assay test showed that the 3h and 8h recoveries of the erythromycin capsules prepared by Examples 1-3 were higher than those of the erythromycin capsules prepared by the methods of Comparative Examples 1-5, and also higher than the positive control, indicating that the erythromycin capsules prepared by the method of the present invention are better absorbed and have a higher drug recovery rate.

[0089] Table 2

[0090] Group 8h recovery rate (%) 3h recovery rate (%) Example 1 90.2 79.1 Example 2 91.3 79.3 Example 3 91.4 80.1 Comparative Example 1 85.3 69.0 Comparative Example 2 85.6 70.2 Comparative Example 3 84.9 69.4 Comparative Example 4 85.0 71.5 Comparative Example 5 85.5 70.8 Positive Control 85.5 72.4

[0091] In summary, the cyclic erythromycin nanocrystal freeze-dried powder is added to the raw materials of the present invention, and the cyclic erythromycin nanocrystal freeze-dried powder adopts cyclic erythromycin to drip polyethylene glycol 1000 vitamin E succinate aqueous solution and poloxamer 188 aqueous solution, and is stirred and dissolved with glycerol, and is pre-frozen, frozen, and dried. The cyclic erythromycin nanocrystal freeze-dried powder prepared by this operation step has a high dissolution rate, and the drug is taken with capsules to avoid the stimulation of the drug to the intestinal tract, which is beneficial to the absorption of the drug and improves the recovery rate of the drug. At the same time, the capsule sealing technology is adopted to avoid the deterioration of the drug in a humid environment, so that the particle size of the drug and the auxiliary materials is mixed, and the stability of the drug is increased. In the comparative example, the erythromycin nanocrystalline freeze-dried powder was replaced with erythromycin, or the preparation method of the erythromycin nanocrystalline freeze-dried powder was changed. The dissolution rates of the comparative drug at 5min, 20min, 35min and 45min were significantly reduced, indicating that the erythromycin capsules prepared by the raw materials, proportions and methods of the present invention were stable in nature. The raw materials polyethylene glycol 1000 vitamin E succinate and poloxamer 188 were used to prepare the erythromycin nanocrystalline freeze-dried powder, which increased the dissolution rate of the drug and improved the absorption and utilization of the drug.

[0092] 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 principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A highly efficient dissolution cyclic erythromycin capsule, characterized in that: The invention comprises the following raw materials in parts by weight: 70-80 parts of erythromycin cyclic ester nanocrystalline freeze-dried powder, 5-7 parts of lactose, 3-5 parts of sodium carboxymethyl starch, 3-5 parts of sodium lauryl sulfate and 2-4 parts of magnesium stearate.

2. A highly effective dissolution cyclic erythromycin capsule according to claim 1, characterized in that: The preparation process of erythromycin cyclic ester nanocrystalline freeze-dried powder includes: S1. Weigh erythromycin cycloheximide, add it to polyethylene glycol 1000 vitamin E succinate aqueous solution and poloxamer 188 aqueous solution to obtain mixed solution I; S2, stirring and homogenizing the mixed solution I to obtain a cyclic erythromycin nanosuspension; S3. Add glycerol to the erythromycin cyclic ester nanosuspension, stir to dissolve, pre-freeze, and freeze-dry to obtain erythromycin cyclic ester nanocrystalline freeze-dried powder.

3. A highly effective dissolution cyclic erythromycin capsule according to claim 2, characterized in that: S1, the volume fractions of the polyethylene glycol 1000 vitamin E succinate aqueous solution and the poloxamer 188 aqueous solution are 0.4-0.6% and 0.2-0.3% respectively, and the mass volume ratio of erythromycin cyclic ester, polyethylene glycol 1000 vitamin E succinate, poloxamer 188 and water is (5-8) g: (0.25-0.35) g: (0.1-0.2) g: (45-50) mL.

4. A highly efficient dissolution cyclic erythromycin capsule according to claim 2, characterized in that: S2, the stirring speed is 5500-6000 rpm, the time is 20-35 min, the temperature is 10-30°C, the homogenization is 1-2 times, and the pressure is 800-850 bar.

5. A highly effective dissolution cyclic erythromycin capsule according to claim 2, characterized in that: S3, the volume fraction of glycerol is 2-4%, the pre-freezing temperature is -80 to -85°C and the pre-freezing time is 30-36h, and freeze-drying is performed after pre-freezing, the freezing temperature is -90 to -100°C and the drying time is 30-35h.

6. The method for preparing the high-efficiency dissolution cyclic erythromycin capsules according to claim 1, characterized in that: The following steps are involved: S1. Divide the erythromycin cyclic ester nanocrystalline freeze-dried powder into two parts to obtain erythromycin cyclic ester nanocrystalline freeze-dried powder I and erythromycin cyclic ester nanocrystalline freeze-dried powder II; S2, centrifugally crushing lactose, sodium carboxymethyl starch, sodium lauryl sulfate, and magnesium stearate, respectively, and sieving to obtain an auxiliary material mixture; S3, mixing the erythromycin cyclic ester nanocrystal freeze-dried powder I and the auxiliary material mixture, stirring to obtain a primary mixed drug; S4. Mix the erythromycin cyclic ester nanocrystalline freeze-dried powder II and the primary mixed drug, stir, perform high shear wet granulation, dry, and use capsule filling and sealing to prepare erythromycin cyclic ester capsules.

7. The method for preparing a highly efficient dissolution cyclic erythromycin capsule according to claim 6, characterized in that: S1, the mass ratio of the erythromycin cyclic ester nanocrystalline freeze-dried powder I and the erythromycin cyclic ester nanocrystalline freeze-dried powder II is (5-10): (65-70).

8. The method for preparing a highly efficient dissolution cyclic erythromycin capsule according to claim 6, characterized in that: S2, the centrifugal grinding, the centrifugal speed is 800-1000rpm, and the grinding particle size is 120-140 microns.

9. The method for preparing a highly efficient dissolution cyclic erythromycin capsule according to claim 6, characterized in that: S3, S4, the mixing, the barrel speed is 12-15rpm, the blade speed is 30-35rpm, the mixing time is 5-8min, the stirring is magnetic stirring, the speed is 300-400rpm, and the time is 20-30min.

10. The method for preparing a highly efficient dissolution cyclic erythromycin capsule according to claim 6, characterized in that: S4, the capsules are filled and sealed, the viscosity of the coating liquid is 135-140 mPa·s, the sealing speed is 65-70 r / min, the number of sealing is 2 times, and after sealing, the capsules are placed at a temperature of 10-25° C. and a relative humidity of 30-40% for drying for 3.5-4.5 hours.

Images