CN112546016A - Enteric hollow cellulose capsule and preparation method thereof - Google Patents
Enteric hollow cellulose capsule and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an enteric hollow cellulose capsule which comprises the following components in percentage by weight: hydroxypropyl methylcellulose phthalate: 45-60% of hydroxypropyl methylcellulose: 25-40% of agar: 5.5-10%, potassium chloride: 0.5-1%, tween-80: 0.5-3% of water in balance; wherein, the hydroxypropyl methylcellulose phthalate is Hp55S or Hp55, and the hydroxypropyl methylcellulose is HPMC-E4. The preparation method of the enteric hollow cellulose capsule does not use any organic solvent, and the enteric hollow cellulose capsule can be prepared by one-step molding by adopting a general hollow capsule production line. The capsule membrane of the hollow capsule has smooth and elastic surface, has the characteristics of no swelling, no disintegration and no leakage of the medicament within 2h in a simulated gastric fluid environment, and complete disintegration and medicament release within 1h or even within 30min in a simulated intestinal fluid environment, and the product has qualified elasticity and friability, good mechanical property of the capsule membrane and good tolerance to the environment.
Description
Technical Field
The invention belongs to the technical field of pharmaceutic adjuvants, and particularly relates to an enteric hollow cellulose capsule and a preparation method thereof.
Background
The empty capsule is divided into a stomach-soluble type, an enteric-soluble type and a colon type, and is respectively corresponding to the regions of the stomach, the small intestine and the colon of a human body to disintegrate and release the medicine. The enteric capsule has the characteristics of being stable in stomach and disintegrating and releasing medicines in small intestine areas of human bodies, and is particularly suitable for filling medicines which are easily damaged by enzyme or gastric acid in stomach and medicines which can strongly stimulate gastric mucosa.
Currently, enteric hollow capsules used clinically are prepared by taking gelatin of animal origin or hydroxypropyl methylcellulose of plant origin as capsule wall materials to prepare blastulas of the hollow capsules, and then coating the outer layer of the blastulas of the hollow capsules by using enteric coating materials such as cellulose phthalate series and acrylic resin EuS100 and EuL100 series to prepare the enteric hollow capsules which are stable in gastric juice and are disintegrated in intestinal juice. The preparation technology of the enteric hollow capsule has the following problems:
the enteric coating solution contains a large amount of organic solvent. Common enteric coating materials such as cellulose phthalate series, acrylic resin EuS100 and EuL100 series are all insoluble in water, and are generally dissolved by ethanol, acetone or mixed organic solvents to prepare enteric coating liquid, and the coating layer adheres the coating materials to the outer layer of the blastula by means of quick volatilization of the organic solvents. A large amount of organic solvents have great potential safety hazards to operators and production workshops.
② a special enteric hollow capsule production line needs to be customized. The preparation process generally comprises the steps of firstly preparing the blastocyst of the hollow capsule, and then immersing the blastocyst into enteric coating liquid for enteric coating, namely the process of dipping glue for many times for forming. Such a process does not allow for the use of a common hollow capsule production line.
And thirdly, the coating times are generally 2-4. Because the enteric coating solution has no coagulability, the forming of the enteric coating layer on the outer layer of the blastula is realized by the volatilization of an organic solvent in the enteric coating solution, and for the purpose of rapid forming, the coating solution is generally prepared by a low-concentration coating material and a high-concentration organic solvent, so that secondary, tertiary or even quaternary coating operation is generally adopted.
CN201910254934.0 granted by Chinese patent discloses an invention patent named as 'hydroxypropyl methylcellulose enteric empty capsule gelated by calcium salt and sodium salt'. This patent is clearly written in the summary of the invention: step 1-step 6 are preparing empty capsule blastula prepared by glue solution comprising hydroxypropyl methylcellulose, gel, calcium salt, sodium alginate and the like; and 7, soaking the capsule rod obtained in the step 6 into an organic solution of hypromellose phthalate again for secondary glue dipping, and forming an enteric coating layer outside the capsule rod. Therefore, CN201910254934.0 discloses a method for preparing a calcium salt and sodium salt gelled hypromellose enteric empty capsule, which essentially uses an organic solution of hypromellose phthalate as an enteric coating solution, and carries out enteric coating molding on a capsule blank through volatilization of an organic solvent by a secondary dipping molding process, and does not really solve the three technical problems of the preparation of the enteric empty cellulose capsule.
Disclosure of Invention
The invention aims to solve the technical problem of providing an enteric hollow cellulose capsule which has the characteristics of no swelling, no disintegration and no leakage of a medicament within 2h in a simulated gastric fluid environment and complete disintegration and medicament release within 1h or even within 30min in a simulated intestinal fluid environment and a preparation method thereof aiming at the defects of the prior art.
The technical scheme adopted by the invention for solving the technical problems is as follows: an enteric hollow cellulose capsule, the weight percentage composition of the hollow capsule is: hydroxypropyl methylcellulose phthalate: 45-60% of hydroxypropyl methylcellulose: 25-40% of agar: 5.5-10%, potassium chloride: 0.5-1%, tween-80: 0.5-3% of water in balance; wherein, the hydroxypropyl methylcellulose phthalate is Hp55S or Hp55, and the hydroxypropyl methylcellulose is HPMC-E4.
The enteric hollow cellulose capsule takes Hp55S or Hp55 as a main capsule wall material, has good acid resistance stability, takes agar as a gel also has good acid resistance stability, takes HPMC-E4 as a capsule wall material to adjust the disintegration speed of the capsule in a simulated intestinal juice environment, and reduces the product cost.
The enteric hollow cellulose capsule has the characteristics of no swelling, no disintegration and no drug leakage in a simulated gastric juice environment for 2 hours, and complete disintegration and drug release in a simulated intestinal juice environment within 1 hour even within 30 min. The enteric hollow cellulose capsule has good capsule membrane mechanical property, and the hollow capsule has good tolerance to the environment through sample observation.
A preparation method of enteric hollow cellulose capsules comprises the following steps:
(1) preparing hydroxypropyl methylcellulose phthalate glue solution A: dissolving 9-16 parts of Hp55S or Hp55 in 30-50 parts of water containing ammonia water, wherein the mass volume ratio of Hp55S or Hp55 to the ammonia water is (6-7.5): 1, stirring at room temperature, and standing for more than 4-8 hours to obtain clear and transparent hydroxypropyl methylcellulose phthalate liquid A;
(2) preparing agar/hydroxypropyl methylcellulose mixed glue solution B: weighing 1.2-1.6 parts of agar, soaking in 50-70 parts of water, standing overnight, and heating and boiling until the agar is dissolved to form an agar glue solution; weighing 1-7 parts of HPMC-E4, 0.12-0.16 part of potassium chloride and 0.1-0.2 part of Tween-80, uniformly mixing the HPMC-E4, the potassium chloride and the Tween-80, pouring the mixture into an agar solution at 90-100 ℃, uniformly stirring and dispersing the materials, and reducing the temperature of a glue solution to 50-55 ℃ under stirring to obtain an agar/hydroxypropyl methylcellulose mixed glue solution B;
(3) preparing the composite cellulose enteric-coated glue solution: heating the hydroxypropyl methylcellulose phthalate glue solution A to 50-55 ℃, pouring the heated hydroxypropyl methylcellulose phthalate glue solution A into the agar/hydroxypropyl methylcellulose mixed glue solution B at 50-55 ℃, uniformly stirring, putting the obtained glue solution into a glue maintaining barrel, maintaining the temperature at 50 ℃ for over 6 hours to obtain a composite cellulose enteric glue solution, and using the composite cellulose enteric glue solution within 24 hours;
(4) dipping glue to prepare embryos: immersing a capsule mold with a proper type into the composite cellulose enteric-coated glue solution at the ambient temperature of 20-25 ℃ and the humidity of 50-65% to dip the glue solution to prepare a blastocyst, and turning the blastocyst up and down for 540-degree shaping to obtain the blastocyst;
(5) drying and pulling out the shell: placing the blastocyst in an oven at 25-35 ℃, after 2-3 h of ventilation drying, pulling out the capsule shell from the capsule mold, cutting edges, sleeving and inspecting the quality to obtain the enteric hollow cellulose capsule, wherein the hollow capsule comprises the following components in percentage by weight: hydroxypropyl methylcellulose phthalate: 45-60% of hydroxypropyl methylcellulose: 25-40% of agar: 5.5-10%, potassium chloride: 0.5-1%, tween-80: 0.5-3% of water in balance; wherein, the hydroxypropyl methylcellulose phthalate is Hp55S or Hp55, and the hydroxypropyl methylcellulose is HPMC-E4.
In the preparation method of the enteric hollow cellulose capsule, no organic solvent is used for preparing the hydroxypropyl methylcellulose phthalate glue solution A, and potential safety hazard caused by the organic solvent does not exist. The preparation method of the enteric hollow cellulose capsules adopts a one-step forming technology, has no special requirements on a production line, and can realize the mass production of the enteric hollow cellulose capsules by adopting a general hollow capsule production line.
Compared with the prior art, the invention has the following advantages:
1) the enteric hollow cellulose capsule consists of Hp55S or Hp55, HPMC-E4, agar, potassium chloride, Tween-80 and water, the raw materials are medical auxiliary materials collected and carried in Chinese pharmacopoeia, and the product meets the main technical index regulation of the enteric hollow capsule in 2020 edition of Chinese pharmacopoeia; the enteric hollow cellulose capsule has the characteristics of no swelling, no disintegration and no drug leakage in simulated gastric juice environment for 2 hours, and complete disintegration and drug release in simulated intestinal juice environment within 1 hour and even within 30 min; in addition, the enteric hollow cellulose capsule has good capsule membrane mechanical properties, and the hollow capsule has good tolerance to the environment through sample observation;
2) the preparation of the enteric hollow cellulose capsule does not use any organic solvent and has no organic solvent pollution;
3) the preparation method of the enteric hollow cellulose capsule has universality, the enteric hollow cellulose capsule can be prepared by one-step forming of a general hollow capsule production line, and a technical worker can easily master the preparation method;
4) the enteric hollow cellulose capsule and the preparation method thereof well solve two problems of the existing enteric hollow cellulose capsule preparation, and are beneficial to promoting the industrial upgrading of the enteric hollow capsule.
Drawings
FIG. 1 is an external view of an enteric hollow Hp55S capsule of example 1;
FIG. 2 is an appearance view of the enteric hollow Hp55S/HPMC capsule of example 2;
FIG. 3 is an SEM image of enteric hollow Hp55S capsules of example 1;
FIG. 4 is an SEM image of enteric hollow Hp55S/HPMC capsules of example 2;
FIG. 5 is an infrared spectrum of the enteric hollow Hp55S capsules of example 1 and the enteric hollow Hp55S/HPMC capsules of example 2;
FIG. 6 is a DSC of enteric-coated Hp55S empty capsules of example 1 and enteric-coated empty Hp55S/HPMC capsules of example 2;
FIG. 7 is the mechanical test results of the enteric hollow Hp55S capsules of example 1;
FIG. 8 shows the mechanical test results of the enteric hollow Hp55S/HPMC capsule of example 2.
Detailed Description
The invention is described in further detail below with reference to the accompanying examples.
Firstly, dissolving a capsule forming material hydroxypropyl methylcellulose phthalate of the enteric hollow cellulose capsule, which is the key for preparing the enteric hollow capsule. 16g of Hp55S was weighed out and dissolved in 100mL of water containing different amounts of ammonia, stirred and left to stand, and the effect of the amount of ammonia on the solubility of Hp55S and the properties of the glue solution was observed, and the results are shown in Table 1.
TABLE 1 Effect of ammonia dosage on Hp55S solubility and dope Properties
As can be seen from Table 1, 16g of Hp55S was dissolved, and if the amount of ammonia water was small, the time required for preparing the glue solution was long and the glue solution was easily whitened when heated to 50 ℃, indicating that part of Hp55S was precipitated after heating; if the ammonia water is used in a large amount, the obtained glue solution has a deep color. Comprehensively considering, the amount of ammonia water needed for dissolving 16g of Hp55S is selected to be 2.4-2.6 mL, the pH value of the prepared glue solution is proper at 6-7 at normal temperature and 25 ℃, and the pH value of the glue solution is 6-6.5 at 50 ℃.
And secondly, screening the gel of the enteric hollow cellulose capsules. Because the Hp55S glue solution has no coagulability, k-carrageenan and low-acyl gellan gum are usually added as gelling agents in the preparation of the plant hollow capsules, and agar is also rarely selected as the gelling agent to promote the plant glue solution to be coagulated and formed on a capsule mould. The formula is as follows: 16g of Hp55S, 1.2g of gelling agent and 100mL of water (containing 2.4mL of ammonia water), Hp55S glue solution containing three different gelling agents is prepared, the influence of the three gelling agents on the Hp55S glue solution and the encapsulation property of the enteric hollow capsule is compared, and the result is shown in Table 2.
TABLE 2 influence of different gelling agents on the encapsulation of Hp55S gelatin solution and enteric hollow capsule
The compatibility of the common gel agent k-carrageenan and low-acyl gellan gum with the Hp55S glue solution is poor, and the glue solution with uniform appearance is difficult to prepare. Meanwhile, the k-carrageenan loses the gel property in the Hp55S glue solution. The agar has good compatibility with Hp55S, and can form uniform transparent glue solution, and the agar can promote Hp55S glue solution to solidify and form on a mold.
And thirdly, compounding capsule wall materials of the enteric hollow cellulose capsules. Hp55S is used as a capsule forming material of the enteric hollow capsule, agar is used as a gelling agent to prepare the enteric hollow cellulose capsule, and the enteric hollow cellulose capsule is stable in simulated gastric juice and can be disintegrated in intestinal juice within 25-60 min. In addition, Hp55S has a high raw material cost. Therefore, two cellulose materials, namely Hp55S and HPMC-E4 (hereinafter referred to as HPMC) are compounded to achieve the purposes of shortening the disintegration time of the product in intestinal juice and reducing the preparation cost of the capsule. The formula is as follows: 1.6g of agar, 0.16g of KCl, 0.2g of Tween-80 and 100mL of water, ammonia water required for dissolving Hp55S is added according to the mass/volume ratio of the two to be 6.67/1, the mass ratio of Hp55S/HPMC compounding is changed (the sum of the two is kept to be 16 g), the influence of the compounding of Hp55S and HPMC on the properties of glue solution and hollow capsules is compared, and the result is shown in Table 3.
TABLE 3 influence of compounding Hp55S with HPMC on the properties of gelatin solution and hollow capsules
With the increase of the proportion of the HPMC, the compatibility of two cellulose glue solutions is in a decreasing trend, when the HPMC reaches or exceeds 50 percent, the viscosity of the glue solution is increased sharply, and uniform glue solution is difficult to form and is pasty. The Hp55S/HPMC (m/m) is controlled to be between 10/6 and 9/7 properly in combination with the uniformity of glue solution, the fluency of the embryo making process, the stability of the capsule in gastric juice and the disintegration speed of the capsule in intestinal juice.
And fourthly, selecting the dosage of the gel agent agar in the enteric hollow cellulose capsule. The agar has the function of promoting the molding of the enteric cellulose glue solution on the mold. Agar has good stability in gastrointestinal tract, and can not meet the formability requirement of glue solution with small dosage, and the dosage can affect the glue dipping process and possibly prolong the disintegration time of the hollow capsule in intestinal juice. The formula is as follows: 9g Hp55S, 7g HPMC, 0.2g tween-80, 1.3mL ammonia water, 100mL water, the dosage of potassium chloride is 10% of agar. The effect of agar dosage on the encapsulation of the gelatin solution and the empty capsules is shown in Table 4.
TABLE 4 influence of agar dosage on the properties of cellulose enteric-coated gelatin solution and hollow capsule
The agar dosage mainly influences the viscosity of the glue solution, the forming speed of the glue solution on a mould and the disintegration speed of the prepared capsule in intestinal juice. The experimental result shows that the concentration of the gel is preferably 1.4 g-1.6 g, and the corresponding glue solution forming time and the disintegration time limit of the capsule are both appropriate.
And fifthly, the influence of gel culture time on the gel solution in the preparation process of the enteric hollow cellulose capsule. The formula is as follows: 9g Hp55S, 7g HPMC, 1.6g agar, 0.16g KCl, 0.2g Tween-80, 1.3mL ammonia water, 100mL water. The viscosity and color of the glue solution were measured by curing at 50 ℃ and the results are shown in Table 5.
TABLE 5 influence of gel incubation time on gel solution
As can be seen from Table 5, the color of the glue solution is stable with the extension of glue maintaining time, but the viscosity of the glue solution tends to increase, probably because the viscosity of the glue solution increases due to water evaporation; secondly, the solubility of Hp55S may be reduced due to ammonia volatilization. Therefore, the glue solution is preferably used within 24 hours.
And sixthly, the influence of the glue dipping temperature in the preparation process of the enteric hollow cellulose capsule. The formula is as follows: 9g Hp55S, 7g HPMC, 1.6g agar, 0.16g KCl, 0.05g Tween-80, 100mL water, 1.3mL ammonia. Respectively culturing at 45 deg.C, 50 deg.C and 55 deg.C, and dipping in glue to make embryo. The results of the effect of the dipping temperature of the gum solution on the preparation of the hollow capsules are shown in Table 6.
TABLE 6 influence of dipping temperature of glue solution on preparation of empty capsules
When the temperature is lower than 45 ℃, the viscosity of the glue solution can be increased, and when the temperature is higher than 55 ℃, the viscosity of the glue solution can be reduced, and the glue solution can turn white and turbid, which is not beneficial to glue dipping. The viscosity is too high, the phenomenon of wire drawing can occur during glue dipping, and the capsule top wall of the obtained hollow capsule can be thicker and has the problems of bark wrinkle, plum blossom head and the like; when the viscosity is too low, the obtained hollow capsule is thin, the phenomena of head collapse, breakage and the like can occur, and the capsule forming rate of the hollow capsule is directly influenced. The dipping temperature is also a key point for producing the empty capsules. The dipping temperature of the hollow capsule is controlled at 50 ℃ by integrating the factors of the viscosity of the glue solution, the uniformity of the glue solution, the thickness of the capsule film, the capsule forming rate and the like.
And seventhly, preparing the enteric hollow cellulose capsule. Four batches of enteric hollow cellulose capsules of different formulation compositions, i.e. example 1 to example 4, were prepared according to the formulations in table 7. The preparation method of the enteric hollow cellulose capsule comprises the following steps:
(1) preparation of Hp55S glue solution A: weighing Hp55S according to the formula in the table 7, dissolving the Hp55S in 30 parts of water containing ammonia water, stirring the mixture evenly at room temperature, and standing the mixture overnight to obtain clear and transparent Hp55S glue solution A with the pH value of 6.5-6.8;
(2) preparing agar/HPMC mixed glue solution B: weighing 1.6 parts of agar, soaking in 70 parts of water, standing overnight, and after the agar is fully swelled, heating and boiling until the agar is dissolved into a transparent agar glue solution; weighing 1-7 parts of HPMC, 0.16 part of potassium chloride and 0.2 part of Tween-80, uniformly mixing to obtain a mixed material, pouring the mixed material into all prepared agar solutions at 90-100 ℃, uniformly stirring and dispersing the materials, and reducing the temperature of a glue solution to 50-55 ℃ under stirring for heat preservation to obtain a transparent or milky turbid agar/HPMC mixed glue solution B;
(3) preparing the composite cellulose enteric-coated glue solution: heating the Hp55S glue solution A to 50-55 ℃, pouring the mixture into the agar/HPMC mixed glue solution B at 50-55 ℃, uniformly mixing, maintaining the glue at 50 ℃ for more than 6 hours to obtain the composite cellulose enteric glue solution, wherein the glue solution is dipped in glue within 6-24 hours.
(4) Dipping glue to prepare embryos: under the conditions that the environmental temperature is 22-25 ℃ and the humidity is 50-65%, soaking a No. 0 capsule mold into 50 ℃ composite cellulose enteric-coated glue solution to dip glue to prepare a blastocyst, wherein the glue dipping speed is 3 plates/min, and turning over the model from top to bottom for 540-degree shaping to obtain the blastocyst; and (3) drying the blastocyst in an oven at 28-35 ℃ for 2h, standing at room temperature for balancing, pulling out the capsule shell from the capsule mold, cutting edges, and sleeving to obtain the enteric hollow cellulose capsule.
(5) Drying and pulling out the shell: and (3) placing the blastocyst in an oven at 28-35 ℃, ventilating and drying for 2h, standing at room temperature for balancing, pulling out the capsule shell from the capsule mold, cutting edges, and sleeving to obtain the enteric hollow cellulose capsule.
(6) Quality inspection of the enteric hollow cellulose capsules: according to the standards of the 'enteric capsule' in the section IV of the Chinese pharmacopoeia 2020, the detection results of key indexes are shown in the table 7.
TABLE 7 enteric hollow cellulose capsule preparation of different formulations (No. 0 capsule mold)
Fig. 1 is an appearance view of the enteric hollow Hp55S capsule of example 1, and fig. 2 is an appearance view of the enteric hollow Hp55S/HPMC capsule of example 2. As can be seen from the comparison between FIG. 1 and FIG. 2, the enteric hollow Hp55S capsule has better transparency than the enteric hollow Hp55S/HPMC capsule.
Fig. 3 is an SEM image of the enteric hollow Hp55S capsule of example 1, and fig. 4 is an SEM image of the enteric hollow Hp55S/HPMC capsule of example 2. Under an electron microscope with 8000 times magnification, the Hp55S, the HPMC and the agar which are three materials have good compatibility, and the capsule membrane surface uniformity is good. The small white spots presented in the figure are likely due to incomplete dissolution of the agar of the gelling agent or crystallization of the coagulant potassium chloride.
Ketoprofen was filled into each enteric empty capsule prepared in example 1 and example 2 at a dose of 50mg to obtain a ketoprofen enteric capsule. The determination is carried out according to the method in the dissolution test item of the ketoprofen enteric capsule in the section II of the Chinese pharmacopoeia 2020, and the results of the dissolution determination and comparison of the two ketoprofen enteric capsules are shown in the table 8. The ketoprofen enteric capsules obtained by filling ketoprofen into the two enteric hollow capsules have the drug dissolution amount of less than 10 percent in gastric juice, which shows that the two enteric hollow cellulose capsules can well protect the filled drugs in the gastric juice; the dissolution amount of the medicine is more than 85% in 45min of intestinal juice, which shows that the dissolution of the two enteric hollow cellulose capsules in a specified dissolution medium meets the requirements of pharmacopoeia.
Table 8 dissolution test comparison of enteric empty capsules filled with ketoprofen (n ═ 6)
| Sample (I) | Enteric hollow Hp55S capsule | Enteric hollow Hp55S/HPMC capsule |
| Simulated drug dissolution amount/%, |
0.31±0.11 | 0.11±0.02 |
| The dissolution amount of the medicine in simulated intestinal juice is/%, and the pH value is 6.8 | 88.39±0.03 | 89.54±0.03 |
FIG. 5 is an infrared spectrum (IR spectrum) of the Hp55S empty capsule of example 1 and the enteric-coated Hp55S/HPMC capsule of example 2. The 5 curves from top to bottom in fig. 5 represent the IR spectra of HPMC, Hp55S, agar, enteric hollow Hp55S capsules, enteric hollow Hp55S/HPMC capsules, respectively. As can be seen from fig. 5: the IR spectrum of the enteric hollow Hp55S capsule is the superposition of the IR spectrum of Hp55S and the IR spectrum of agar, and the compatibility of the two is good; the IR spectrum of the enteric hollow Hp55S/HPMC capsule contains three main components of Hp55S, HPMC and agar, and the three components are reflected to have good compatibility.
Fig. 6 is DSC images of the enteric hollow Hp55S capsules of example 1 and the enteric hollow Hp55S/HPMC capsules of example 2. As can be seen from fig. 6: the exothermic peak temperature of Hp55S is 69.84 deg.C, the exothermic peak temperature of agar is 92.58 deg.C, and the exothermic peak temperature of enteric hollow Hp55S capsule is 81.14 deg.C, and the proportion of agar in the capsule formula is about 7%, so that the stability of enteric hollow Hp55S capsule is improved compared with Hp 55S. The exothermic peak temperature of the enteric hollow Hp55S/HPMC capsule is 93.08 ℃, while the exothermic peak temperatures of Hp55S, HPMC and agar are 69.84 ℃, 89.42 ℃ and 92.58 ℃, respectively, which are lower than that of the enteric hollow Hp55S/HPMC capsule, reflecting that the three components are compatible, improving the stability of the enteric hollow Hp55S/HPMC capsule and reflecting that the enteric hollow Hp55S/HPMC capsule is more stable than the Hp55S hollow capsule.
Fig. 7 and 8 are the mechanical test results of the enteric hollow Hp55S capsule of example 1 and the enteric hollow Hp55S/HPMC capsule of example 2, respectively. Table 9 shows the film mechanical property test results of the enteric hollow Hp55S capsules of example 1 and the enteric hollow Hp55S/HPMC capsules of example 2, wherein the tensile rate is 10 mm/min.
TABLE 9 mechanical property test of enteric hollow capsule membrane
| Kinds of capsular sac | Film thickness × Width × Length/mm | Maximum force/N | Percent by stretching ratio% | Tensile strength/MPa |
| Enteric hollow Hp55S capsule envelope | 0.11×10×100 | 57.37±0.90 | 2.67±0.29 | 50.51±2.24 |
| Enteric hollow Hp55S/HPMC capsule membrane | 0.11×10×100 | 47.33±2.34 | 3.0±0.5 | 43.03±2.13 |
From table 9 and fig. 7 and 8, it can be derived: compared with the enteric hollow Hp55S/HPMC capsule, the tensile rate and tensile strength of the enteric hollow Hp55S capsule are superior to those of the enteric hollow Hp55S/HPMC capsule, but the mechanical property of the enteric hollow Hp55S/HPMC capsule membrane can also meet the requirement of practical application.
Table 10 shows the comparison of water vapor transmission of the capsule membranes of the enteric hollow Hp55S capsule of example 1 and the enteric hollow Hp55S/HPMC capsule of example 2.
TABLE 10 comparison of water vapor permeability of enteric hollow capsule membranes
| Sample (I) | Enteric hollow Hp55S capsule | Enteric hollow Hp55S/HPMC capsule membrane |
| Water vapor transmission rate/g/(m)2.24h) | 207.13±33.42 | 292.82±24.78 |
As can be seen from Table 10, the water vapor transmission rate of the enteric hollow Hp55S/HPMC capsule was greater than that of the enteric hollow Hp55S capsule film. This is due to the inclusion of HPMC in the enteric hollow Hp55S/HPMC capsules, suggesting that the enteric hollow Hp55S/HPMC capsules need to be sealed and stored with plastic bags of a certain thickness.
From the results of the tests shown in tables 7 to 10 and FIGS. 1 to 8, it can be seen that the capsule film has the following properties in appearance, disintegration time, dissolution rate, IR, DSC, mechanical properties, and water vapor transmission rate: the performance index of the enteric hollow Hp55S/HPMC capsule prepared by adopting the composite Hp55S/HPMC capsule material meets the requirements of Chinese pharmacopoeia on the enteric hollow capsule, and is superior to the enteric hollow Hp55S capsule prepared by only taking Hp55S as the capsule material in the aspects of intestinal tract disintegration, production cost and the like.
Claims (2)
1. An enteric hollow cellulose capsule is characterized in that the weight percentage of the hollow capsule is as follows: hydroxypropyl methylcellulose phthalate: 45-60% of hydroxypropyl methylcellulose: 25-40% of agar: 5.5-10%, potassium chloride: 0.5-1%, tween-80: 0.5-3% of water in balance; wherein, the hydroxypropyl methylcellulose phthalate is Hp55S or Hp55, and the hydroxypropyl methylcellulose is HPMC-E4.
2. A preparation method of an enteric hollow cellulose capsule is characterized by comprising the following steps:
(1) preparing hydroxypropyl methylcellulose phthalate glue solution A: dissolving 9-16 parts of Hp55S or Hp55 in 30-50 parts of water containing ammonia water, wherein the mass volume ratio of Hp55S or Hp55 to the ammonia water is (6-7.5): 1, stirring at room temperature, and standing for more than 4-8 hours to obtain clear and transparent hydroxypropyl methylcellulose phthalate liquid A;
(2) preparing agar/hydroxypropyl methylcellulose mixed glue solution B: weighing 1.2-1.6 parts of agar, soaking in 50-70 parts of water, standing overnight, and heating and boiling until the agar is dissolved to form an agar glue solution; weighing 1-7 parts of HPMC-E4, 0.12-0.16 part of potassium chloride and 0.1-0.2 part of Tween-80, uniformly mixing the HPMC-E4, the potassium chloride and the Tween-80, pouring the mixture into an agar solution at 90-100 ℃, uniformly stirring and dispersing the materials, and reducing the temperature of a glue solution to 50-55 ℃ under stirring to obtain an agar/hydroxypropyl methylcellulose mixed glue solution B;
(3) preparing the composite cellulose enteric-coated glue solution: heating the hydroxypropyl methylcellulose phthalate glue solution A to 50-55 ℃, pouring the heated hydroxypropyl methylcellulose phthalate glue solution A into the agar/hydroxypropyl methylcellulose mixed glue solution B at 50-55 ℃, uniformly stirring, putting the obtained glue solution into a glue maintaining barrel, maintaining the temperature at 50 ℃ for over 6 hours to obtain a composite cellulose enteric glue solution, and using the composite cellulose enteric glue solution within 24 hours;
(4) dipping glue to prepare embryos: immersing a capsule mold with a proper type into the composite cellulose enteric-coated glue solution at the ambient temperature of 20-25 ℃ and the humidity of 50-65% to dip the glue solution to prepare a blastocyst, and turning the blastocyst up and down for 540-degree shaping to obtain the blastocyst;
(5) drying and pulling out the shell: placing the blastocyst in an oven at 25-35 ℃, after 2-3 h of ventilation drying, pulling out the capsule shell from the capsule mold, cutting edges, sleeving and inspecting the quality to obtain the enteric hollow cellulose capsule, wherein the hollow capsule comprises the following components in percentage by weight: hydroxypropyl methylcellulose phthalate: 45-60% of hydroxypropyl methylcellulose: 25-40% of agar: 5.5-10%, potassium chloride: 0.5-1%, tween-80: 0.5-3% of water in balance; wherein, the hydroxypropyl methylcellulose phthalate is Hp55S or Hp55, and the hydroxypropyl methylcellulose is HPMC-E4.
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Effective date of registration: 20230103 Address after: No. 788, Qihang South Road, Yinzhou Economic Development Zone, Ningbo, Zhejiang 315140 Patentee after: Ningbo Jiangnan Capsule Co.,Ltd. Address before: 315100, Qian 8, Yinzhou District, Ningbo, Zhejiang, Hunan Road Patentee before: ZHEJIANG WANLI University |