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

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


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


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 35oC to 250oC with nitrogen flow 20 mL·min-1 and heating rate 10oC·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 25oC 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.

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.