Pulullan enteric hollow capsule and preparation method thereof

Abstract

The invention discloses a pullulan enteric hollow capsule and a preparation method, and belongs to the field of biological medicine manufacturing, and the preparation method comprises the following steps: pre-treating part of pullulan; the preparation method comprises the following steps: dissolving pretreated pullulan, unpretreated pullulan and auxiliary materials in distilled water at 75-95 DEG C, stirring and dissolving, and standing at 45-60 DEG C for 8-12 hours to form a glue solution; cooling the glue solution to 40-50 DEG C, dipping in glue for forming, drying for 50-200 minutes at 25-45 DEG C under the humidity of 30-60%, demolding, cutting and sleeving; and sequentially carrying out spray polishing by using a sodium alginate solution and a calcium chloride solution to prepare the enteric hollow capsule. The pullulan enteric hollow capsule obtained by the invention has the disintegration rate of less than or equal to 7.7% in simulated gastric juice within 2 hours, has good acid resistance, has the dissolution rate of more than or equal to 98% in simulated intestinal juice within 60 minutes, and has good drug release property and friability resistance.

Description

Technical Field

[0001] The present invention relates to the field of biopharmaceutical manufacturing, and in particular to a pullulan enteric-coated hollow capsule and a preparation method thereof. Background Art

[0002] Capsule preparations are widely used in clinical drug delivery. Enteric-coated hollow capsules, in particular, can effectively mask drug odor, achieve targeted intestinal release, and avoid drug irritation to the gastric mucosa, making them ideal vehicles for the delivery of powdered or granular drugs. Existing enteric-coated hollow capsules are primarily categorized as gelatin-based and plant-based, both of which have significant drawbacks: gelatin-based capsules are prone to cross-linking with drugs, while plant-based capsules are highly brittle in low-humidity environments and require complex manufacturing.

[0003] Pullulan is a suitable candidate material to replace hard capsules. It is an ideal alternative material due to its excellent film-forming properties, non-toxicity, odorlessness, biodegradability, solubility, and transparency. However, the mechanical properties and enteric stability of single pullulan capsules are insufficient. Summary of the Invention

[0004] Technical problems solved: In response to the technical problems existing in the prior art, the present invention provides a pullulan enteric-coated hollow capsule and a preparation method, which solves the above problems by compounding the pretreatment process with specific excipients and combining the double solution polishing technology.

[0005] Technical solution: The preparation method of the pullulan enteric-coated hollow capsules of the present invention comprises the following steps: Step 1: pretreat part of the pullulan polysaccharide by adding 0.25-2.25 kg of NaIO4 and 0-100 L of deionized water to every 1 kg of pullulan polysaccharide, stirring and dissolving in the dark, then dialyzing and freeze-drying; Step 2: dissolving the pretreated pullulan, unpretreated pullulan, and excipients in distilled water at 75-95°C, stirring to dissolve, and then standing at 45-60°C for 8-12 hours to form a glue solution; the excipients are selected from one or more of fucoidan, carboxymethyl chitosan, and gellan gum, and the amount of each excipient added is 0-5% of the total glue solution mass; Step 3: Cool the glue liquid to 40-50℃, dip it into the glue and shape it, dry it at 25-45℃ and 30-60% humidity for 50-200min, demould and cut it, and then fit it together; Step 4: spray polishing with sodium alginate solution and calcium chloride solution in sequence to prepare enteric-coated hollow capsules.

[0006] Preferably, in step 2, the total amount of pullulan is 5-15% of the mass of the glue, and the pretreated pullulan accounts for 0-10% of the total amount of pullulan.

[0007] Preferably, the sodium alginate solution is prepared from sodium alginate, CMC-Na and glycerol; and the calcium chloride solution is prepared from CaCl2 and ethanol.

[0008] Preferably, the polishing order of the sodium alginate solution and the calcium chloride solution in step 4 is not interchangeable.

[0009] The present invention also discloses a pullulan enteric-coated hollow capsule, which is prepared by the above method, has a 2-hour disintegration rate of ≤8% in simulated gastric fluid, a 60-minute dissolution rate of ≥90% in simulated intestinal fluid, and a friability of ≤2%.

[0010] Compared with the prior art, the present invention has the following beneficial effects: The present invention adopts pullulan as a film-forming agent, adds excipients such as fucoidan, carboxymethyl chitosan and gellan gum, and adopts sodium alginate and calcium chloride polishing to prepare enteric-coated hollow capsules, and the capsule forming rate is ≥99% (Example 1, Example 5, Example 7). Experiments have confirmed that the obtained enteric-coated hollow capsules have a disintegration rate of ≤7.7% in simulated gastric fluid for 2 hours (Example 1), have good acid resistance, and a dissolution rate of ≥98% in simulated intestinal fluid for 60 minutes (Example 1, Example 3, Example 6), have good drug release and anti-brittleness, and can be widely used in the field of capsule preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 The hollow capsule preparation process of the present invention is shown in FIG. DETAILED DESCRIPTION

[0012] To make the purpose, technical solutions and advantages of the present invention clearer, the following Figure 1 The technical solution of the present invention is clearly and completely described. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field are within the scope of protection of the present invention.

[0013] like Figure 1 As shown, the present invention discloses a method for preparing a pullulan enteric-coated hollow capsule, comprising: (1) Pre-treating a portion of pullulan: adding 0.25-2.25 kg of NaIO4 and 0-100 L of deionized water to every 1 kg of pullulan, stirring to dissolve in the dark, then dialyzing and freeze-drying; (2) dissolving pretreated pullulan, unpretreated pullulan, and excipients in distilled water at 75-95° C., stirring to dissolve, and then standing at 45-60° C. for 8-12 hours to form a glue solution; the excipients are selected from one or more of fucoidan, carboxymethyl chitosan, and gellan gum, and the amount of each excipient added is 0-5% of the total glue solution mass; wherein the total amount of pullulan is 5-15% of the glue solution mass, and the pretreated pullulan accounts for 0-10% of the total pullulan amount; (3) Cool the glue solution to 40-50°C, dip the glue into the mold, dry it at 25-45°C and 30-60% humidity for 50-200 minutes, demould and cut it, and then fit it together; (4) spray polishing with sodium alginate solution and calcium chloride solution in sequence to prepare enteric-coated hollow capsules; wherein the sodium alginate solution is prepared from sodium alginate, CMC-Na and glycerol; the calcium chloride solution is prepared from CaCl2 and ethanol; the polishing order of the sodium alginate solution and the calcium chloride solution is not interchangeable.

[0014] The present invention also discloses a pullulan enteric-coated hollow capsule, which is prepared by the above method, has a 2-hour disintegration rate of ≤8% in simulated gastric fluid, a 60-minute dissolution rate of ≥90% in simulated intestinal fluid, and a friability of ≤2%.

[0015] Example 1: Pullulan pretreatment process: Take 1kg pullulan, add 0.25kg NaIO4 and 50L deionized water, stir in the dark for 2h, dialyze for 48h and then freeze-dry. Pretreated pullulan (accounting for 5% of the total pullulan amount), untreated pullulan (15% of the glue mass) and 2% fucoidan, 1% carboxymethyl chitosan, 2.2% gellan gum are placed in a sol tank and dissolved in 90℃ distilled water (glue: water = 1:3). After vacuum degassing, stand at 60℃ for 10h to form a glue. The glue is cooled to 40℃, dipped in glue and formed, dried at 35℃ and 45% humidity for 120min, and fitted after demoulding and cutting. The sodium alginate solution contains 1% sodium alginate, 0.5% CMC-Na, and 0.5% glycerol; the calcium chloride solution contains 5% CaCl2 in 75% ethanol; the sodium alginate solution and the calcium chloride solution are spray-polished in sequence with an interval of ≤5 minutes to prepare enteric-coated hollow capsules.

[0016] Example 2: Pullulan pretreatment process: Take 1kg pullulan, add 0.25kg NaIO4 and 50L deionized water, stir in the dark for 2h, dialyze for 48h and then freeze-dry. Pretreated pullulan (accounting for 5% of the total pullulan amount), untreated pullulan (15% of the glue mass) and 2% fucoidan, 0.2% carboxymethyl chitosan, 2.2% gellan gum are placed in a sol tank and dissolved in 90℃ distilled water (glue: water = 1:3). After vacuum degassing, stand at 60℃ for 10h to form a glue. The glue is cooled to 40℃, dipped in glue and formed, dried at 35℃ and 45% humidity for 120min, and fitted after demoulding and cutting. The sodium alginate solution contains 1% sodium alginate, 0.5% CMC-Na, and 0.5% glycerol; the calcium chloride solution contains 5% CaCl2 in 75% ethanol; the sodium alginate solution and the calcium chloride solution are spray-polished in sequence with an interval of ≤5 minutes to prepare enteric-coated hollow capsules.

[0017] Example 3: Pullulan pretreatment process: Take 1kg pullulan, add 0.25kg NaIO4 and 50L deionized water, stir in the dark for 2h, dialyze for 48h and then freeze-dry. Pretreated pullulan (accounting for 5% of the total pullulan amount), untreated pullulan (15% of the glue mass) and 0.5% fucoidan, 1% carboxymethyl chitosan, 2.2% gellan gum are placed in a sol tank and dissolved in 90°C distilled water (glue: water = 1:3). After vacuum degassing, stand at 60°C for 10h to form a glue. The glue is cooled to 40°C, dipped in glue and formed, dried at 35°C and 45% humidity for 120min, and fitted after demoulding and cutting. The sodium alginate solution contains 1% sodium alginate, 0.5% CMC-Na, and 0.5% glycerol; the calcium chloride solution contains 5% CaCl2 in 75% ethanol; the sodium alginate solution and the calcium chloride solution are spray-polished in sequence with an interval of ≤5 minutes to prepare enteric-coated hollow capsules.

[0018] Example 4: Pullulan pretreatment process: Take 1kg of pullulan, add 0.25kg of NaIO4 and 50L of deionized water, stir in the dark for 2h, dialyze for 48h, and then freeze-dry. Pretreated pullulan (accounting for 5% of the total pullulan amount), untreated pullulan (15% of the glue mass), 2% fucoidan, 1% carboxymethyl chitosan, and 2.2% gellan gum are placed in a sol tank and dissolved in 90℃ distilled water (glue: water = 1:3). After vacuum degassing, stand at 60℃ for 10h to form a glue. The glue is cooled to 40℃, dipped in glue and formed. Dry at 35℃ and 45% humidity for 120min, demolded and cut, and then fitted. Use sodium alginate solution spray polishing, the sodium alginate solution contains 1% sodium alginate, 0.5% CMC-Na, and 0.5% glycerol to prepare enteric-coated hollow capsules.

[0019] Example 5: Pullulan pretreatment process: Take 1kg pullulan, add 0.25kg NaIO4 and 50L deionized water, stir in the dark for 2h, dialyze for 48h and then freeze-dry. Pretreated pullulan (accounting for 5% of the total pullulan amount), untreated pullulan (15% of the glue mass) and 2% fucoidan, 1% carboxymethyl chitosan, 2.2% gellan gum are placed in a sol tank and dissolved in 90℃ distilled water (glue: water = 1:3). After vacuum degassing, stand at 60℃ for 10h to form a glue. The glue is cooled to 40℃, dipped in glue and formed, dried at 35℃ and 45% humidity for 120min, and fitted after demoulding and cutting. The sodium alginate solution contains 1% sodium alginate, 0.5% CMC-Na, and 0.5% glycerol; the calcium chloride solution contains 5% CaCl2 in 75% ethanol; the calcium chloride solution and the sodium alginate solution are spray-polished in sequence with an interval time of ≤5 minutes to prepare enteric-coated hollow capsules.

[0020] Example 6: Pullulan pretreatment process: Take 1kg of pullulan, add 0.5kg NaIO4 and 100L deionized water, stir in the dark for 2h, dialyze for 48h and then freeze-dry. Pretreated pullulan (accounting for 5% of the total pullulan amount), untreated pullulan (15% of the glue mass) and 2% fucoidan, 1% carboxymethyl chitosan, 2.2% gellan gum are placed in a sol tank and dissolved in 95°C distilled water (glue: water = 1:3). After vacuum degassing, stand at 50°C for 11h to form a glue. The glue is cooled to 50°C, dipped in glue and formed, dried at 45°C and 30% humidity for 90min, and fitted after demoulding and cutting. The sodium alginate solution contains 1% sodium alginate, 0.5% CMC-Na, and 0.5% glycerol; the calcium chloride solution contains 5% CaCl2 in 75% ethanol; the sodium alginate solution and the calcium chloride solution are spray-polished in sequence with an interval of ≤5 minutes to prepare enteric-coated hollow capsules.

[0021] Example 7: Pullulan pretreatment process: Take 1kg pullulan, add 0.25kg NaIO4 and 50L deionized water, stir in the dark for 2h, dialyze for 48h and then freeze-dry. Pretreated pullulan (accounting for 5% of the total pullulan amount), untreated pullulan (15% of the glue mass) and 2% fucoidan, 1% carboxymethyl chitosan, 2.2% gellan gum are placed in a sol tank and dissolved in 75°C distilled water (glue: water = 1:3). After vacuum degassing, stand at 45°C for 12h to form a glue. The glue is cooled to 45°C, dipped in glue and formed, dried at 25°C and 60% humidity for 200min, and fitted after demoulding and cutting. The sodium alginate solution contains 1% sodium alginate, 0.5% CMC-Na, and 0.5% glycerol; the calcium chloride solution contains 5% CaCl2 in 75% ethanol; the sodium alginate solution and the calcium chloride solution are spray-polished in sequence with an interval of ≤5 minutes to prepare enteric-coated hollow capsules.

[0022] Comparative Example 1: Pullulan pretreatment process: Take 1kg of pullulan, add 0.25kg NaIO4 and 50L deionized water, stir in the dark for 2h, dialyze for 48h and then freeze-dry. Put the pretreated pullulan (accounting for 5% of the total pullulan), untreated pullulan (10% of the glue mass) and 1% carboxymethyl chitosan and 2.2% gellan gum into a sol tank and dissolve them in 90℃ distilled water (glue: water = 1:3). After vacuum degassing, let it stand at 60℃ for 10h to form a glue. Cool the glue to 40℃, dip it in glue and shape it. Dry it at 35℃ and 45% humidity for 50min, demold and cut it and then fit it together. The sodium alginate solution contains 1% sodium alginate, 0.5% CMC-Na, and 0.5% glycerol; the calcium chloride solution contains 5% CaCl2 in 75% ethanol; the sodium alginate solution and the calcium chloride solution are spray-polished in sequence with an interval of ≤5 minutes to prepare enteric-coated hollow capsules.

[0023] Comparative Example 2: Untreated pullulan (10% of the total mass of the gelatin solution), 2% fucoidan, 1% carboxymethyl chitosan, and 2.2% gellan gum were dissolved in 90°C distilled water (gelatin:water = 1:3) in a gelatinization tank. After vacuum degassing, the gelatin solution was allowed to stand at 60°C for 10 hours to form a gelatin solution. The gelatin solution was cooled to 40°C, dipped into the gelatin solution, and then dried at 35°C and 45% humidity for 120 minutes. The gelatin solution was then cut and molded, and then fitted. A sodium alginate solution containing 1% sodium alginate, 0.5% CMC-Na, and 0.5% glycerol was used; a calcium chloride solution containing 5% CaCl2 in 75% ethanol was used. Enteric-coated hollow capsules were then spray-polished sequentially with the sodium alginate solution and the calcium chloride solution, with an interval of ≤5 minutes.

[0024] According to the preparation methods of Examples 1 to 7 and Comparative Examples 1 to 2, 100 capsule caps and capsule bodies were prepared respectively, and the capsule formation rates were statistically analyzed. The statistical results are shown in Table 1.

[0025] Table 1 Capsulation rate (%) of Example 1 to Example 7 and Comparative Example 1 to Comparative Example 2: sample Cyst formation rate / % Example 1 99 Example 2 92 Example 3 86 Example 4 98 Example 5 99 Example 6 96 Example 7 99 Comparative Example 1 82 Comparative Example 2 89 .

[0026] As shown in Table 1, adding an appropriate amount of fucoidan to the gel solution helps to improve the encapsulation rate of enteric-coated capsules. Fucoidan, as a sulfated polysaccharide derived from brown seaweed, can interact with other colloids, and this interaction leads to changes in rheological properties. The addition of fucoidan helps to improve the elastic modulus and shear properties of the gel solution. Therefore, the appropriate addition of fucoidan helps to form capsules.

[0027] A certain amount of acetaminophen powder was filled into enteric-coated hollow capsules prepared in Examples 1 to 7 and Comparative Examples 1 to 2, as well as commercially available enteric-coated hollow capsules, 6 capsules each, with each capsule filled with 0.45 g of acetaminophen powder; the filled enteric-coated acetaminophen capsules were placed in 900 ml of simulated gastric fluid for dissolution testing, and samples (5 ml) were taken at 30 min, 60 min, 90 min, and 120 min for acetaminophen drug concentration testing. The test results are shown in Table 2; after sampling, an equal amount of simulated gastric fluid was promptly supplemented.

[0028] The drug release of acetaminophen in simulated gastric fluid = [(acetaminophen concentration in simulated gastric fluid) / 5×900 / 100]×100%.

[0029] Table 2 Test results of acetaminophen drug concentration in simulated gastric fluid of Examples 1-7, Comparative Examples 1-2 and commercially available enteric-coated capsules (mg / ml): project 30min 60min 90 minutes 120 minutes Commercially available enteric-coated capsules 2.2 4.6 5.9 8.6 Comparative Example 1 2.3 4.6 6.4 9.1 Comparative Example 2 2.8 4.7 7.0 9.5 Example 1 1.5 3.1 5.3 7.7 Example 2 1.9 3.6 5.5 7.9 Example 3 1.9 4.0 5.8 8.2 Example 4 1.6 24 53 89 Example 5 1.6 7.9 26 64 Example 6 1.5 3.5 5.5 8.0 Example 7 1.4 3.4 5.3 7.8 .

[0030] After the simulated gastric fluid dissolution test was completed, the sample was immediately transferred to a dissolution apparatus containing 900 ml of simulated intestinal fluid for dissolution testing. Samples (5 ml) were taken at 30 min, 60 min, 90 min, and 120 min for acetaminophen concentration testing. The test results are shown in Table 3. After sampling, an equal amount of simulated intestinal fluid was promptly replenished.

[0031] The drug release of acetaminophen in simulated intestinal fluid = [(acetaminophen concentration in simulated intestinal fluid) / 5×900 / 100]×100%.

[0032] Table 3 Test results of acetaminophen drug concentration in simulated intestinal fluid of Examples 1 to 7, Comparative Examples 1 to 2, and commercially available enteric-coated capsules (mg / ml): project 10min 20min 30min 60min Commercially available enteric-coated capsules 70 82 89 93 Comparative Example 1 68 83 90 94 Comparative Example 2 70 82 88 93 Example 1 81 87 93 98 Example 2 74 84 91 96 Example 3 73 86 92 98 Example 4 - - - - Example 5 - - - - Example 6 84 90 95 98 Example 7 66 80 88 95 .

[0033] It can be seen from Tables 2 and 3 that the appropriate addition of sodium alginate contributes to the acid resistance of enteric-coated capsules. In addition, the use of sodium alginate solution and calcium chloride solution in the polishing process can form a layer of calcium alginate film on the capsule surface, thereby enhancing the acid resistance of the capsule.

[0034] A certain amount of Chinese medicinal powder was filled into the enteric-coated hollow capsules prepared in Examples 1 to 7 and Comparative Examples 1 to 2, as well as commercially available enteric-coated hollow capsules, to prepare capsule preparations each filled with 0.45 g of Chinese medicinal powder. 50 capsules of each of the above-prepared capsule preparations were taken and placed one by one into a glass tube (inner diameter 24 mm, length 200 mm) erected on a wooden board (2 cm thick bottom). A cylindrical weight (made of polytetrafluoroethylene, diameter 22 mm, weighing 20±0.1 g) was freely dropped from the mouth of the glass tube to observe whether the capsules were broken. If broken, no more than 5 capsules were allowed to break. The test results are shown in Table 4.

[0035] Table 4 Friability test results of Examples 1-7, Comparative Examples 1-2 and commercially available enteric-coated capsules: sample friability Commercially available enteric-coated capsules 5 / 50 Comparative Example 1 0 / 50 Comparative Example 2 8 / 50 Example 1 0 / 50 Example 2 2 / 50 Example 3 2 / 50 Example 4 0 / 50 Example 5 0 / 50 Example 6 1 / 50 Example 7 0 / 50 .

[0036] As shown in Table 4, after filling with medicinal powder, the friability ratio of the enteric-coated capsules of Examples 1 to 7 is the best among the capsule samples, which indicates that pretreatment of pullulan can effectively improve the friability of the capsules, and a higher dose of carboxymethyl chitosan is beneficial to the improvement of friability; pullulan is a natural degradable macromolecular microbial polysaccharide extracted from the fermentation medium of Aureobasidium pullulans, and has good degradability, adhesion, antioxidant properties, film-forming properties, and biocompatibility. The nine hydroxyl groups on its main chain can be chemically modified to form a large number of derivatives, thereby improving its mechanical and biological properties. The friability of enteric-coated hollow capsules can be reduced by oxidizing the hydroxyl groups on the pullulan main chain to aldehyde groups and introducing carboxymethyl chitosan to react with amino groups to undergo Schiff base reaction to enhance the mechanical properties.

[0037] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing pullulan enteric-coated hollow capsules, characterized in that: The following steps are involved: Step 1: pretreat part of the pullulan polysaccharide by adding 0.25-2.25 kg of NaIO4 and 0-100 L of deionized water to every 1 kg of pullulan polysaccharide, stirring and dissolving in the dark, then dialyzing and freeze-drying; Step 2: dissolving the pretreated pullulan, unpretreated pullulan, and excipients in distilled water at 75-95°C, stirring to dissolve, and then standing at 45-60°C for 8-12 hours to form a glue solution; the excipients are selected from one or more of fucoidan, carboxymethyl chitosan, and gellan gum, and the amount of each excipient added is 0-5% of the total glue solution mass; Step 3: Cool the glue liquid to 40-50℃, dip it into the glue and shape it, dry it at 25-45℃ and 30-60% humidity for 50-200min, demould and cut it, and then fit it together; Step 4: spray polishing with sodium alginate solution and calcium chloride solution in sequence to prepare enteric-coated hollow capsules.

2. The method for preparing pullulan enteric-coated hollow capsules according to claim 1, wherein In step 2, the total amount of pullulan is 5-15% of the mass of the glue solution, and the pretreated pullulan accounts for 0-10% of the total amount of pullulan.

3. The method for preparing the pullulan enteric-coated hollow capsule according to claim 1, wherein The sodium alginate solution is prepared from sodium alginate, CMC-Na and glycerol; the calcium chloride solution is prepared from CaCl2 and ethanol.

4. The pullulan enteric-coated hollow capsule and preparation method according to claim 1, characterized in that: The polishing order of the sodium alginate solution and the calcium chloride solution in step 4 cannot be interchanged.

5. A pullulan enteric-coated hollow capsule, characterized in that: The invention is prepared by the method according to any one of claims 1 to 4, has a disintegration rate of ≤8% in simulated gastric fluid within 2 hours, a dissolution rate of ≥90% in simulated intestinal fluid within 60 minutes, and a friability of ≤2%.

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