Study on Enteric Vacant Capsules Based on Hydroxypropyl Methylcellulose Phthalate-55S

Liping L

Research Article

Ann Materials Sci Eng. 2021; 5(1): 1038.

Study on Enteric Vacant Capsules Based on Hydroxypropyl Methylcellulose Phthalate-55S

Liping L*

College of Biological & Environmental Sciences, Zhejiang Wanli University, Ningbo, China

*Corresponding author: Liu Liping, College of Biological & Environmental Sciences, Zhejiang Wanli University, Ningbo, 315100, China

Received: June 04, 2021; Accepted: June 25, 2021; Published: July 02, 2021

Abstract

The formulation and preparation technology of enteric cellulose hollow capsules were studied, and its properties were evaluated. The enteric cellulose hollow capsules were prepared with hydroxypropyl methylcellulose phthalate~55S (Hp55S) as film~forming material, agar as molding agent and hydroxypropyl methylcellulose (HPMC) as disintegration regulator. The preparation process was as follows: (1) At room temperature, 9~16 phr of Hp55S was dissolved in 30~50 phr of dilute ammonia solution with pH of 10~11 to obtain transparent Hp55S glue solution; (2) Put 1.2~1.6 parts of agar into 50~70 parts of water, heat and boil to obtain agar solution. 1~7 phr of HPMC, 0.12~0.16 phr of KCl and 0.1~0.2 phr of Tween~80 were poured into agar solution to disperse evenly, and then the temperature of gel solution was reduced to 50~55 oC to obtain agar/HPMC mixed gel solution; (3) The Hp55S solution was heated to 50~55 oC and then poured into agar/HPMC solution to obtain composite cellulose solution. The temperature of the solution was kept at 50~55 oC. (4) Enteric cellulose hollow capsules were prepared by dipping in glue, shaping, drying, trimming and assembling. The results showed that the enteric cellulose hollow capsules met the quality requirements of “enteric coated hollow capsules” in Chinese Pharmacopoeia. Compared with the traditional formula and preparation process of enteric coated hollow capsules, it avoids the use of organic solvents and multiple molding process. The enteric cellulose hollow capsule greatly reduces the preparation cost from the formula to the process, which is green, safe and environmental friendly, and has good application value.

Keywords: Hydroxypropyl methylcellulose phthalate-55S (Hp55S); Hydroxypropyl Methylcellulose (HPMC); Agar; Non organic solvents; One-step molding process; Enteric cellulose hollow capsules

Introduction

Vacant capsules can be divided into gastric type, enteric type and colon type, respectively corresponding to the human stomach, small intestine and colon regional administration. The enterosoluble vacant capsules have the characteristics of stable in the stomach and disintegrating in the small intestine of human body [1]. It is especially suitable for filling drugs which are easily damaged by enzymes or acid in the stomach and produce strong irritation to gastric mucosa [2]. There are three processes for the preparation of drug enteric capsules: (1) Firstly, the drug particles or pellets are coated with enteric coated materials, and then they are filled into ordinary vacant capsules [3,4]; (2) The enteric coating solution is sprayed on the outer layer of the capsule filled with drugs [5]. (3) The drug is directly filled into the enteric empty capsules [6-8]. The first and second enteric coated drug capsules are actually made by uniformly spraying the intestinal solution on the surface of drug particles or capsules through coating process. The process has the problem of potential impact of coating solvents on drugs. The third preparation of drug enteric capsule is to fill the drug directly into the enteric empty capsule. The third preparation of drug enteric capsule is that the drug is directly filled in the enterosoluble vacant capsule, which can avoid the potential influence of organic solvent in the coating solution on the filling drug. Therefore, it is necessary to develop enterosoluble vacant capsules.

At present, the enterosoluble vacant capsules usually use gelatin or hydroxypropyl methylcellulose as raw materials to prepare blastocysts, and then the enteric coated materials are used to coat the outer layer of blastocysts [9]. This technology has the following problems:

• The preparation process is complex [10]. Generally, vacant blastocysts are prepared, and then the blastocysts are inserted into the enteric coated solution for coating again. This requires a customized professional production line.

• There are a lot of organic solvents in the enteric coating solution. The commonly used enteric coating materials, such as cellulose phthalate series [11] and acrylic resin series [12], are usually insoluble in water, but easily soluble in ethanol, acetone or mixed organic solvents. The coating material is attached to the outer layer of vacant blastocyst by the volatilization of organic solvent. A large number of organic solvents have great safety risks to operators and production workshops.

In order to solve the above technical problems, a common cellulose enteric coated materia---hydroxypropyl methylcellulose phthalate-55S (Hp55S) was selected as the membrane material of enteric cellulose vacant capsules. This material has good acid stability and has been widely used as pharmaceutical excipients [13,14]. According to the characteristic that Hp55S could be dissolved in the medium with pH more than 5.5 [15], ammonia solution was selected to dissolve Hp55S to prepare Hp55S glue. Ammonia is a weak basic substance, which has little effect on the stability of Hp55S and can be removed by volatilization in the subsequent drying process of capsules. Agar was used as a gelling agent of Hp55S gum, agar also had good acid stability [16], which could promote the solidification of Hp55S glue on the mold.

In this study, the preparation of Hp55S glue solution does not use organic solvent, and there is no hidden danger of organic solvent in the production process. The enteric vacant capsules can be prepared by one-step dipping process, and the ordinary vacant capsule production line can meet the preparation requirements [8]. The enteric cellulose vacant capsules prepared has the stability of no swelling and no disintegration in simulated gastric juice for 2 hours, and complete disintegration in simulated intestinal fluid within 30 minutes, and has sufficient pliability and has good tolerance to the environment.

Materials and Methods

Raw materials and chemicals

Hydroxypropyl methylcellulose phthalate (Hp55S, 202004027, Zhejiang Deqing Weikang Biotechnology Co., Ltd.); Hydroxypropyl methylcellulose (HPMC, E4 type, 20190911, Zhejiang prospect Pharmaceutical Co., Ltd.); κ- carrageenan (refined gum, 0909, Zhaoqing Haixing Biotechnology Co., Ltd.); Jieleng gum (TW-JY800 type, m200707, Zhejiang Tianwei Biochemical Engineering Co., Ltd.); Agar strip (food grade, content 99%, Henan Runcheng Chemical Industry Co., Ltd.); Tween-80 (CP, 20190322, Sinopharm Group Chemical Reagent Co., Ltd.); Ammonia (AR, Sinopharm Group Chemical Reagent Co., Ltd.); Glycerin(Food grade, Lianyungang Youjin food additive development Co., Ltd); Potassium chloride (food grade); Ketoprofen enteric-coated capsules(No.190402, Peking University Pharmaceutical Co., Ltd).

(1) Preparation of Hp55S glue solution: To dissolve Hp55S in water containing ammonia, mix well and place overnight to obtain a clear and transparent glue solution with pH value of 6.5~6.8.

(2) Preparation of HPMC/agar glue solution: The agar was soaked in water and heated until clear and transparent. HPMC, KCl and Tween-80 were mixed evenly, the mixture was dispersed in agar solution, and the mixed glue was cooled to 50 ⁰C.

(3) Preparation of enteric cellulose glue: the temperature of Hp55S glue was raised to 50⁰C, and then it was poured into HPMC/ agar glue at the same temperature, and then mixed evenly. The enteric cellulose glue was obtained by keeping the temperature at 50⁰C. The glue solution was used to make capsule within 6~24 hours.

4) Preparation of capsule: Under the environment temperature of 22~25 ⁰C and relative humidity of 50~65 %, the mold of No.1 capsule was immersed in the enteric cellulose glue solution of 45~50 ⁰C. The dipping speed was 3 molds/min, and it was turned up and down 540⁰ for shaping. The capsules were dried in an oven at 28~35 ⁰C for 2 h, and then removed from the capsule mold. After cutting and nesting, the enteric cellulose vacant capsules were obtained. Record the solidification time of the glue on the mold surface (subject to the glue on the mold does not stick to the hand) [10]. The defective products such as shrinkage head, bubble eye, bark wrinkle and damage in the capsules were removed, and the qualified rate of the prepared capsules was calculated [17].

Determination of properties of glue solution and hollow capsules

Properties of glue solution: Viscosity of glue (cP): DV-VISCOMETER (Brookfield) was selected. The rotor S62 was preheated and the number of turns was adjusted to twist 30~70 % at a certain temperature.

pH value of glue : It was determined by pH meter-8601, AZ instrument Corp.).

Color of glue: Tu-1810 UV-Vis spectrophotometer (Beijing puxi General Instrument Co., Ltd.) was used to determine the absorbance value of glue at 540nm wavelength.

Properties of hollow capsule: Capsule film thickness (mm): Six points on the capsule shell were randomly selected to measure, and the average value was taken.

Moisture content (%): MB35 moisture analyzer (OHAUS Instrument Co., Ltd.) was selected for determination. The capsule (the cap body of the vacant capsule separated) was put in the moisture analyzer for 2 h under 105⁰C.

Gastric stability and intestinal disintegration: Four use tablet analyzer (SY-2D, Shanghai Huanghai drug testing instrument Co., Ltd.) was used. Six vacant capsules were filled with talcum powder. According to the method of “enterosoluble vacant gelatin capsules” in Chinese Pharmacopoeia 2020 edition [18].

Brittleness and tightness: According to the method of “enterosoluble vacant gelatin capsules” in Chinese Pharmacopoeia 2020 edition [18].

SEM: The enteric vacant capsule film was directly pasted on the conductive tape and adhered to the sample table. The surface structure of the film was observed by GSM 6360 scanning electron microscope (Japan Electronics Co., Ltd.) to analyze whether the components were compatible.

IR: The samples were dried and ground into powder under liquid nitrogen. KBr tablet pressing method was used and Vertex 70 Fourier infrared spectrometer (Bruker Instruments Co., Ltd.) was used to determine the compatibility of the components.

DSC: DSC 131 EVO differential scanning calorimetry (Sataram Instruments Co., Ltd.) was used to scan the film from 35^oC to 250^oC with nitrogen flow 20 mL·min^-1 and heating rate 10^oC·min^-1 to judge the compatibility of components and the thermal stability of the membrane.

Mechanical property: Enteric cellulose hollow capsule film was prepared by tape casting method. Thickness×width×length of the film strip was 0.11×10×100 mm, and the tensile rate was 10 mm·min^-1. The shear strength and elongation of the film strip were measured by WOW-05 electronic universal testing machine (Jinan Chuanbai Instrument Equipment Co., Ltd.) under the environment of 25^oC and RH 50% [19].

Water vapor permeability rate: The film (30×30×0.11 mm) was fixed with paraffin wax at the mouth of conical flask containing anhydrous calcium chloride. To weigh it and put it in SYW-350B drug stability test box (Ningbo southeast Instrument Co., Ltd.) at 25oC and RH 75%. After 24h, take it out and weigh again to calculate the water vapor permeability.

$\mathit{Water vapor transmission rate / g / m^{2}}\times 24\mathit{hr}=\frac{\mathit{\bigtriangleup \mathit{m}}}{\mathit{At}}$

Where: Δm/g - the amount of water absorbed by calcium chloride; A/m²-film area; t/24h [20].

Dissolution of ketoprofen enteric capsules: Ketoprofen enteric capsules were obtained by fillings containing ketoprofen (No.190402, Peking University Pharmaceutical Co., Ltd) with Hp55S capsules and Hp55S/HPMC capsules. Each capsule contained 50 mg ketoprofen. The dissolution was determined according to the method of “ketoprofen enteric capsules” in Chinese Pharmacopoeia (2020 Edition) [21].

Results and Discussion

Preparation of Hp55S glue solution

The dissolution of Hp55S material is the key to the preparation of Hp55S glue solution. Weigh 16g of Hp55S was put into 100mL of water containing different amounts of ammonia, mix well and place to observe the effect of the amount of ammonia on the dissolution of Hp55S. The results were shown in Table 1.

Table 1: Effect of ammonia dosage on solubility and gel properties of Hp55S.




  
    Ammonia/mL 
    pH value of aqueous solution 
    Speed of dissolution and    deaeration/h 
    Glue solution/25°C
    Glue solution/50°C
  
  
    Appearance/A540nm 
    Viscosity/cP
    pH value
    Appearance/A540nm 
    Viscosity/cP
    pH value
  
  
    2 
    10 
    Insoluble 
    /
    /
    /
    /
    /
    /
  
  
    2.2 
    10.5 
    >8 
    Clarity    transparency/ 

      0.047 
    748
    5.5
    White    transparent/ 

      0.127 
    339
    4.8
  
  
    2.4 
    10.5 
    4.5 
    Yellowish    transparent/ 

      0.053 
    711 
    6.5 
    Yellowish    transparent/ 

      0.061 
    332 
    6 
  
  
    2.6 
    10.7 
    4 
    Yellowish    transparent/ 

      0.055 
    654 
    7 
    Yellowish    transparent/ 

      0.087 
    283 
    6.5 
  
  
    2.8 
    11 
    2.5 
    Yellow    transparent/ 

      0.058 
    624 
    7.5 
    Yellow    transparent/ 

      0.137 
    256 
    7.2



Table 1: Effect of ammonia dosage on solubility and gel properties of Hp55S.

It could be seen from Table 1 that when the amount of ammonia water was lower, the dissolution time of Hp55S was longer; on the contrary, when the amount of ammonia was more, the dissolution time of Hp55S was shorter, and the color of the glue solution was darker. When the temperature of the glue was increased from 25⁰C to 50⁰C, the color of the glue was turned white and the pH value was increased slightly. It indicates that ammonia in the glue may volatilize a little during heating. The results showed that the amount of ammonia needed to dissolve 16g of Hp55S was 2.4~2.6 mL, and the pH value of the Hp55S gel was 6 ~7 at 25⁰C and 6~6.5 at 50⁰C.

Selection of gel-forming agent

Because cellulose gel itself has no coagulability, k-carrageenanand low acyl gellan gum are usually chosen as gel-forming agent [22,23] to promote the solidification of the colloid in the preparation of cellulose vacant capsules. It has been rarely reported that agar is chosen as gelforming agent for plant vacant capsules. The effects of three kinds of gel-forming agent (dosage of 1.2g) on the gel properties and capsule formability of Hp55S were investigated and compared. The results were shown in Table 2.

Table 2: Effect of different gel-forming agent on the gel properties and capsule formability of Hp55S.




  
    Gel-forming agent 
    Properties of glue 
    Dipping process 
    Capsule thickness
    Yeild/% 
  
  
    De foaming 
    Appearance/50°C
    Viscosity/cP, 50°C
    Glue flowing
    Shaping time/s
    Wall/mm
    Top/mm 
  
  
    k-Carrageenan 
    Hard 
    Non    uniform 

      With    flocs 
    /
    /
    /
    /
    /
    /
  
  
    Low    acyl gellan gum 
    Hard 
    With    flocs 

      mushy 
    /
    /
    /
    /
    /
    /
  
  
    Agar 
    Easy 
    Uniform    Transparency 
    54410 
    No 
    4-6 
    0.11 
    0.16 
    >95%



Table 2: Effect of different gel-forming agent on the gel properties and capsule formability of Hp55S.

The compatibility of commonly used k-carrageenan and low acyl gellan gum with Hp55S was poor, so it was difficult to make a uniform appearance glue. At the same time, k- carrageenan lost gel characteristics in Hp55S solution. Agar had good compatibility with Hp55S solution, which could form a uniform transparent gel. This is because agar has more extensive pH tolerance. Therefore, agar was chosen as coagulant of Hp55S gel on capsule mold.

Compositeing of film materials for enteric cellulose vacant capsules

enteric cellulose vacant capsules prepared with Hp55S as membrane material and agar gel were very stable in simulated gastric juice, but the disintegration time in intestinal juice was about 25~60 min. In addition, the raw material cost of Hp55S was high. Therefore, HPMC and Hp55S were selected to shorten the disintegration time of the capsules in intestinal juice and reduce the preparation cost of the capsules. The effect of the mass ratio of Hp55S/ HPMC (total was 16g) on the properties of gel and capsule was shown in Table 3.

Table 3: Effects of the mass ratio of Hp55S and HPMC on the properties of glue solution and vacant capsules.




  
    Hp55S/HPMC 

      /m/m 
    Properties of glue 
    Dipping process 
    Capsule thickness
    Yeild/% 
    Disintegration time/min
  
  
    Defoaming 
    Appearance/50°C
    Viscosity/cP, 50°C
    Glue flowing
    Setting time/s 
    Wall /mm
    Top /mm
    pH1.2 
    pH6.8 
  
  
    16/0 
    Easy 
    Uniform    transparency 
    544 
    No 
    4-6
    0.11 
    0.16 
    >95 
    >120 
    25-60
  
  
    5-Nov 
    Easy 
    Uniform    Slightly white 
    613 
    No 
    4-6
    0.11 
    0.16 
    >95 
    >120 
    14-52
  
  
    6-Oct 
    Easy 
    Uniform    Slightly white 
    639 
    No 
    4-6
    0.12 
    0.17 
    >95 
    >120 
    10-35
  
  
    7-Sep 
    Easy 
    Uniform    Slightly white 
    685 
    No 
    3-5
    0.11 
    0.17 
    >95 
    >120 
    7-25
  
  
    8-Aug 
    Hard 
    mushy 
    / 
    / 
    / 
    / 
    / 
    / 
    / 
    /



Table 3: Effects of the mass ratio of Hp55S and HPMC on the properties of glue solution and vacant capsules.

enteric cellulose hollow capsule prepared from Hp55S and agar gel was stable in simulated gastric juice, but the disintegration time in intestinal juice was about 25~60 min, and the cost of raw material was high. Therefore, HPMC was selected as the disintegration regulator of enteric hollow capsules in intestinal liquid and the cost of raw materials was reduced. The effects of the mass ratio of Hp55S/HPMC (total mass was 16g) on the properties of the glue solution and hollow capsules were investigated. The results were shown in Table 3.

With the increase of HPMC content in the ratio of Hp55S/ HPMC, the compatibility of the two kinds of cellulose in solution decreased. When HPMC content was more than 50%, the viscosity of the gel increased sharply and it was difficult to form a uniform gel. According to the uniformity of the gel, the stability of the capsule in gastric juice and the disintegration time in intestinal juice, the mass ratio of Hp55S/HPMC should be controlled in the range of 10/6~9/7.

Effect of agar dosage

Agar can promote the formation of composite Hp55S/HPMC glue solution on the mold, and has good stability in gastrointestinal fluid.

The amount of agar mainly affects the viscosity of the glue, the molding speed of the composite Hp55S/HPMC glue solution on the mold, and the disintegration time of the capsule in the intestinal fluid. According to the experimental results, the amount of agar added in every 100 mL of gel solution was 1.4~1.6 g, and the molding time of the prepared gel on the mold was 3~6 s at room temperature. The obtained capsules were stable in gastric juice for more than 2 hours and disintegrated in intestinal fluid within 25 minutes (Table 4).

Table 4: Effect of agar dosage on properties of Hp55S/HPMC glue solution and vacant capsule.




  
    Agar dosage/g 
    Viscosity/cP, 50°C
    Setting time/s
    Capsule thickness
    Yeild/% 
    Disintegration time/min 
  
  
    Wall/mm 
    Top/mm 
    pH1.2 
    pH6.8 
  
  
    1.2 
    600
    4-6
    0.11
    0.16
    >95 
    film    a little swollen 
    8-21
  
  
    1.4
    652
    4-6
    0.11
    0.15
    >95 
    >120 
    8-20
  
  
    1.6
    685
    3-5
    0.12
    0.18
    >95 
    >120 
    7-25
  
  
    1.8
    743
    2-3
    0.12
    0.17
    >95 
    >120 
    9-31
  
  
    2
    773
    2-3
    0.12
    0.18
    >95 
    >120 
    10-35



Table 4: Effect of agar dosage on properties of Hp55S/HPMC glue solution and vacant capsule.

Effect of incubation time on properties of composite glue solution

The formula was as follows: 9g Hp55S, 7g HPMC, 1.6g agar, 0.16g KCl, 0.2g Tween-80, 1.3mL ammonia water and 100mL water. The prepared glue was incubated at 50⁰C, and the effects of incubation time on the viscosity and color of the glue were determined.

It could be seen from Table 5 that the color of the glue solution was basically stable, but the viscosity of the glue solution tended to increase with the extension of incubation time. The reason may be that the evaporation of water or the volatilization of ammonia would lead to the partial precipitation of Hp55S in the glue solution. Therefore, it was better to use the glue within 24 hours.

Table 5: Effect of incubation time on properties of glue.




  
    Incubation time/h
    Viscosity/cP, 50°C
    Color/A540, 50°C
  
  
    6
    742±14
    2.112±0.005
  
  
    9
    856±12
    2.342±0.005
  
  
    12
    984±2
    2.347±0.006
  
  
    24
    1135±23
    2.382±0.004
  
  
    36
    2170±17
    2.370±0.007
  
  
    48
    2860±44
    2.340±0.009



Table 5: Effect of incubation time on properties of glue.

Effect of temperature of glue solution on capsule formation during dipping

The temperature of the glue solution is also the key point for the preparation of vacant capsules. The temperature will affect the viscosity of the glue solution and thus the thickness of the capsule film. The formula was: 9g Hp55S, 7g HPMC, 1.6g agar, 0.16g KCl, 0.05g tween-80, 1.3mL ammonia and 100mL water. The effects of 45⁰C, 50⁰C and 55⁰C glue solution on the preparation of vacant capsule embryo were investigated. The results were shown in Table 6.

Table 6: Laboratory values at hospital admission.




  
    Temperature/°C
    Viscosity/cP
    Uniformity
    Capsule thickness /mm
    Yield/%
    Reasons for unqualified capsules
  
  
    Wall
    Top
  
  
    45
    906±11
    Uniform transparency
    0.12
    0.18
    >92 
    wall too thick
  
  
    50
    685±4
    Uniform whitening
    0.11
    0.17
    >95 
    /
  
  
    55
    544±3
    Uniform whitening
    0.11
    0.16
    >80 
    top too thin



Table 6: Laboratory values at hospital admission.

The glue viscosity decreases with the increase of temperature. At 45~50 ⁰C, the color of the glue was uniform, the viscosity was appropriate, and the thickness of the prepared capsule film was appropriate (0.11~0.12 mm). At 55⁰C, the color of the glue turned white and the viscosity was low. Some of the obtained capsules appeared top thin, shrunken head, rupture, and decreased rate of capsule formation. Therefore, the temperature of glue solution should be controlled at 45~50 ⁰C.

The glue viscosity generally decreases with increasing temperature, because the dissolution temperature of HPMC is generally within 50⁰. It could be seen from experiments that when the temperature of the glue solution was 45~50 ⁰C, the color of the glue solution was uniform, the viscosity was suitable, and the thickness of the prepared capsule film was suitable (0.11~0.12 mm). However, when the temperature of the glue was 50⁰C, the color of the glue was white and the viscosity was low, the qualified rate of capsules prepared with glue at this temperature was reduced, and the tops of some capsules collapsed and broken. Therefore, the temperature of the glue solution should be controlled between 45⁰C and 50⁰C in the dipping process.

Preparation and determination of enteric cellulose vacant capsules

Four batches of enteric cellulose vacant capsules with different formulations were prepared according to Table 7.

Table 7: To preparation of enteric cellulose vacant capsules with different formulations (1#mould).




  
    No
    Formula
    Viscosity/cP, 50°C
    Setting time/s
    Yield/%
    Capsule thickness 

      Wall/top

      /mm
    Degree of tightness

      /10 pills
    Brittleness/50 pills
    Disintegration time/min 
  
  
    Hp55S/g
    HPMC

      /g
    Agar

      /g
    Ammonia

      /mL
    KCl

      /g
    Tween-80

      /g
    H2O

      /mL
    
  
    pH1.2 
    pH6.8 
  
  
    1
    16
    0
    1.2
    2.4
    0.12
    0.2
    100
    644±4
    4-6
    >95
    0.11/0.16
    0/10
    0/50
    >120
    25~60
  
  
    2
    9
    7
    1.6
    1.35
    0.16
    0.2
    100
    626±2
    2-4
    >95
    0.12/0.17
    0/10
    0/50
    >120
    9~25
  
  
    3
    10
    6
    1.6
    1.5
    0.16
    0.2
    100
    686±4
    3-4
    >95
    0.11/0.16
    0/10
    0/50
    >120
    13~36
  
  
    4
    11
    5
    1.6
    1.65
    0.16
    0.2
    100
    755±3
    2-4
    >95
    0.11/0.17
    0/10
    0/50
    >120
    19~47



Table 7: To preparation of enteric cellulose vacant capsules with different formulations (1#mould).

The enteric cellulose vacant capsules prepared according to formula 1 and formula 2 in Table 7 were expressed as Hp55S capsules and Hp55S/HPMC capsules respectively.

Appearance characterization of enteric cellulose vacant capsules: The appearance of Hp55S capsules and Hp55S / HPMC capsules were as follows:

Under the magnification 8000 electron microscope, the white colloidal particles in the SEM image may be caused by incomplete agar dissolution. The SEM images of Hp55S/HPMC capsules were smooth and uniform, indicating that Hp55S, HPMC and agar had good compatibility.

IR spectrum: It could be seen from the infrared spectrum that the infrared spectrum of the Hp55S capsule was the superposition of the two main components of Hp55S and agar, indicating that the two components had good compatibility. The IR spectrum of Hp55S/ HPMC capsules included the IR spectrum information of Hp55S, HPMC and agar, which also reflect that these three components were compatible.

According to the DSC curve, the exothermic peak temperature of Hp55S and agar were 69.84⁰C and 92.58⁰C, respectively, and the proportion of agar in Hp55S capsule was about 7%, while the exothermic peak temperature of enteric vacant capsule of Hp55S capsule was 81.14⁰C, which showed that the thermal stability of Hp55S capsule was improved. The exothermic peak temperature of composite Hp55S/HPMC capsules was 93.08, while the corresponding temperatures of three main components of Hp55S, HPMC and agar were 69.84⁰C, 89.42⁰C and 92.58⁰C, respectively. The results showed that the three components were not only compatible, but also the intermolecular force between the three components were enhanced, which improved the stability of the composite Hp55S/HPMC capsules.

From the comparison of the endothermic peaks, Hp55S/ HPMC capsules were more stable than Hp55S capsules.

Mechanical test of enteric cellulose vacant capsules: The remaining glue solution (45~50 ⁰C) after the capsule preparation in Table 7 was 15g glue solution per plate. The glue solution was poured onto a 20×20 cm polytetrafluoroethylene plate, and the capsule film was prepared by the casting method. Place the film in an oven at 30 ⁰C to dry for 1.5~2 hours, uncover and store the membrane in a drug stable box at 20~25 ⁰C and RH 50% for use. The mechanical properties and water vapor permeability of the membrane were measured.

It could be seen from Table 8 and Figures 1-7 that the maximum force and tensile strength of Hp55S capsule film were higher than those of Hp55S/HPMC capsule film, but the tensile rate of Hp55S/ HPMC capsule film was better than that of Hp55S capsule film. The results showed that the Hp55S/HPMC capsules had more toughness than Hp55S capsules.

Table 8: Mechanical properties test of enteric cellulose films.




  
    Samples
    Thickness× 

      width×length/mm
    Maximum    force/N
    Tensile    rate/%
    Tensile    strength/MPa
  
  
    Formula 1: Hp55S capsule film
    0.11×10×100
    57.37±0.90
    2.67±0.29
    50.51±2.24
  
  
    Formula 2: Complex Hp55S/HPMC capsule film
    0.11×10×100
    47.33±2.34
    3.0±0.5
    43.03±2.13



Table 8: Mechanical properties test of enteric cellulose films.

Figure 1: Preparation process of enteric cellulose glue and hollow capsules.

    
    
    Figure 1: Preparation process of enteric cellulose glue and hollow capsules.

Figure 2: Effect of ammonia dosage on the color and transparency of Hp55S glue (50^oC).

    
    
    Figure 2: Effect of ammonia dosage on the color and transparency of Hp55S
glue (50^oC).

Figure 3: Appearance of Hp55S capsules and Hp55S/HPMC capsules corresponding to formula 1 and 2 of Table 7.

    
    
    Figure 3: Appearance of Hp55S capsules and Hp55S/HPMC capsules
corresponding to formula 1 and 2 of Table 7.

Figure 4: SEM images of Hp55S capsules and Hp55S/HPMC capsules corresponding to formula 1 and 2 of Table 7.

    
    
    Figure 4: SEM images of Hp55S capsules and Hp55S/HPMC capsules corresponding to formula 1 and 2 of Table 7.

Figure 5: Infrared spectrum of Hp55S capsules and Hp55S/HPMC capsules corresponding to formula 1 and 2 of Table 7.

    
    
    Figure 5: Infrared spectrum of Hp55S capsules and Hp55S/HPMC capsules corresponding to formula 1 and 2 of Table 7.

Figure 6: DSC of Hp55S capsules and Hp55S / HPMC capsules corresponding to formula 1 and 2 of Table 7.

    
    
    Figure 6: DSC of Hp55S capsules and Hp55S / HPMC capsules corresponding to formula 1 and 2 of Table 7.

Figure 7: Mechanical test of enteric cellulose films.

    
    
    Figure 7: Mechanical test of enteric cellulose films.

Water vapor permeability: It can be seen from Table 9 that the water vapor transmission rate of composite Hp55S/HPMC enteric vacant capsule film was higher than that of Hp55S enteric vacant capsule film. This is due to the HPMC [24,25] in the composite enteric vacant capsule membrane. It is suggested that the composite Hp55S/ HPMC enteric vacant capsules should be sealed and preserved.

Table 9: Comparison of water vapor permeability of enteric cellulose films of formula 1 and 2 (n=5).




  
    Samples
    Hp55S capsule film
    Hp55S/HPMC capsule film
  
  
    Water vapor    permeability/g/(m2.24h)
    207.13±33.42
    292.82±24.78



Table 9: Comparison of water vapor permeability of enteric cellulose films of formula 1 and 2 (n=5).

Determination of dissolution of ketoprofen enteric capsules: According to the ultraviolet visible spectrophotometry (general rule 0401, Chinese Pharmacopoeia, 2020 Edition), the sample solution, standard solution and blank solution were scanned in the wavelength range of 200~300 nm, and the spectrograms 8 and 9 were obtained.

According to Figure 8 and Figure 9, the absorbance of ketoprofen enteric capsules was determined at 260nm wavelength, and the dissolution amount of ketoprofen in each capsule was calculated. The results are shown in Table 10.

Dissolution medium	Sample	Hp55S capsules	Hp55S/HPMC capsules
Dissolution/%	In simulated gastric liquid (pH=1)	0.31±0.11	0.114±0.023
Dissolution/%	In simulated intestinal liquid (pH=7.2)	88.39±0.033	89.54±0.028

Study on Enteric Vacant Capsules Based on Hydroxypropyl Methylcellulose Phthalate-55S

Abstract

Introduction

Materials and Methods

Raw materials and chemicals

Determination of properties of glue solution and hollow capsules

Results and Discussion

Preparation of Hp55S glue solution

Selection of gel-forming agent

Compositeing of film materials for enteric cellulose vacant capsules

Effect of agar dosage

Effect of incubation time on properties of composite glue solution

Effect of temperature of glue solution on capsule formation during dipping

Preparation and determination of enteric cellulose vacant capsules

Conclusions

Declarations

References