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Characteristics and Application of Hydroxypropyl Methylcellulose (HPMC) Hollow Capsules

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Characteristics and Application of Hydroxypropyl Methylcellulose (HPMC) Hollow Capsules

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      In the hundred-year history of capsules, gelatin has always maintained its status as a mainstream capsule material due to its extensive sources, stable physical and chemical properties and excellent processing properties. As people's preference for capsules increases, hollow capsules are more widely used in the fields of food, medicine and health products.

       However, the occurrence and spread of mad cow disease and foot-and-mouth disease have caused people to worry about products of animal origin. The commonly used raw materials of gelatin are the bones and skins of cattle and pigs, and the risks are gradually attracting attention. In order to reduce the safety risks of hollow capsule raw materials, industry experts continue to research and develop suitable plant-derived capsule materials.

       In addition, with the increase in the variety of capsules, the diversity of its contents has gradually made people realize that gelatin hollow capsules have compatibility problems with some special contents. For example, content containing aldehyde groups or reacting to form aldehyde groups under certain conditions may cause cross-linking of gelatin; content with strong reducing properties may undergo Mailard reaction with gelatin (Mailard Reaction); The highly hygroscopic contents will cause the capsule shell to lose water and lose its original toughness. The stability of the above-mentioned hollow gelatin capsules has caused more attention to the development of new capsule materials.

       Which plant-derived materials are suitable for producing hollow hard capsules? Many attempts have been made. Chinese Patent Document Application No. 200810061238.X applied for sodium cellulose sulfate as the main capsule material; 200510013285.3 applied for starch or starch composition as the main capsule material; Wang GM [1] reported the manufacture of hollow capsules from chitosan capsule materials ; Zhang Xiaoju et al. [2] reported a product with konjac-soybean protein as the main capsule material. Of course, cellulose materials are the most studied. Among them, hollow capsules made of hydroxypropyl methylcellulose (HPMC) have formed large-scale production.

      HPMC is widely used in the field of food and medicine. It is a commonly used pharmaceutical excipient and is included in the pharmacopoeias of various countries; FDA and the European Union approved HPMC as a direct or indirect food additive; GRAS is included as a safe substance, number No. GRN 000213; included in the JECFA database, INS No. 464, does not limit the daily intake of HPMC; in 1997, the Ministry of Health of China approved it as a food additive and thickener (No. 20), suitable for all kinds of food , Add according to production requirements [2-9]. Due to the difference in properties of gelatin, the prescription of HPMC hollow capsules is more complicated, and some gelling agents, such as gum arabic, carrageenan (seaweed), starch, etc. need to be added.

      HPMC hollow capsule is a product with a natural concept. Its material and production process are recognized by the Jewish, Islamic and Vegetarian Associations. It can meet the needs of people of various religions and eating habits and has a high acceptance. In addition, HPMC hollow capsules also have the following unique properties:

Low water content-about 60% lower than gelatin hollow capsules

       The water content of gelatin hollow capsules is generally 12.5%-17.5% [10]. The temperature and humidity of the environment should be controlled within an appropriate range during the production, transportation, use and storage of hollow capsules. The proper temperature is 15-25°C and the relative humidity is 35%-65%, so that the product performance can be maintained for a long time. The water content of HPMC film is very low, generally 4%-5%, which is about 60% lower than the water content of gelatin hollow capsules (Fig 1.). The moisture exchange with the environment during long-term storage will increase the moisture content of HPMC hollow capsules in the specified packaging, but it will not exceed 9% within 5 years.

High toughness, no brittleness

       As mentioned above, the gelatin film has a prescribed moisture content. If it is lower than this limit, the gelatin film will be significantly brittle. Ordinary gelatin hollow capsules without any additives have a risk of brittleness of more than 10% when the moisture content is 10%; when the moisture continues to decrease to 5%, 100% brittleness will appear. In contrast, the toughness of HPMC hollow capsules is much better, and even if the ambient humidity is low, they still maintain good performance (Fig 3). Of course, the incidence of brittleness of HPMC hollow capsules with different prescriptions under low humidity will show great differences. On the contrary, when the gelatin hollow capsule is placed in a high humidity environment, the capsule shell will become soft, deformed, or even collapse after absorbing water. HPMC hollow capsules can maintain good shape and performance even under high humidity conditions. Therefore, HPMC hollow capsules are highly adaptable to the environment. This advantage of HMPC hollow capsules is particularly significant when the product sales area covers a variety of climate zones or the storage conditions are relatively poor.

Strong chemical stability

       The cross-linking reaction of gelatin capsules is a thorny problem encountered in capsule formulations. Since the aldehyde group of the content reacts with the amino group of the amino acid in the gelatin to form a network structure, the capsule shell is difficult to dissolve under the conditions of dissolution in vitro, thereby affecting the release of the drug. Hypromellose is a cellulose derivative that is chemically inert and has excellent compatibility with most substances. Therefore, HPMC hollow capsules have no risk of cross-linking reactions and have high chemical stability.

Good coating performance

       Enteric-coated capsules are used for drugs that are easily destroyed by gastric acid, are irritating to the gastric mucosa, or require targeted administration. The internationally accepted enteric-coated capsule technology is the overall coating of enteric-coated pellets and capsules. HPMC hollow capsules show unique advantages in the overall coating of the capsule.

       Studies have shown that, due to the relatively rough surface of HPMC hollow capsules (Fig 5), the affinity with most enteric coating materials is significantly higher than that of gelatin, and the adhesion speed and uniformity of the coating materials are significantly better than that of gelatin, especially for body cap binding The reliability of the partial coating is significantly improved. In vitro dissolution testing showed that the permeability of HPMC capsules in the stomach is lower after coating, and there is a good release in the intestine [13].

Conclusion

       The characteristics of HPMC hollow capsules make its application fields continue to expand. From all-natural products to moisture-sensitive or hygroscopic contents, there are now unique applications in the field of dry powder inhalants and enteric coatings. It should be noted that the HPMC hollow capsules currently on the market at home and abroad have a relatively high oxygen permeability and a slightly slower disintegration than gelatin hollow capsules, but their bioavailability in vivo is similar [11] and should be considered during research and development.

       As we all know, it takes a long way to go from laboratory research, large-scale testing, industrial production to market promotion. This is why, after years of research and development, only a few hollow capsule products made of plant-derived materials have been successfully launched on the market. In 1997, Capsugel took the lead in listing HPMC hollow capsule VcapsTM in the United States, providing a new choice for oral capsules. At present, the global annual sales volume of HPMC hollow capsules has exceeded 20 billion, and it is growing at an annual rate of 25%.
 

References:

1.Wang GM,Chen CH,Ho HO,et al. Novel design of osmotic chitosan capsules characterized by asymmetric membrane structure for in situ formation of delivery orifice [J]. Int J Pharm,2006,319(122):71 - 81.
2.张小菊,姜发堂. 植物硬空心胶囊成型工艺研究. 食品科技. 2008,33(12):60-62
3.食品添加剂使用卫生标准 GB2760-1996,1997年增补品种,中国卫生部
4.U.S. Food and Drug Administration. CFR 21 172.665.
http://www.access.gpo.gov/nara/cfr/waisidx_08/21cfr172_08.html
5.U.S. Food and Drug Administration. FOOD ADDITIVE STATUS LIST
http://www.cfsan.fda.gov/~dms/opa-appa.html
6.JECFA. 1991. 37th Meeting of the Joint FAO/WHO Expert Committee on Food Additives. World Health Organization, Geneva. FAS, 28, pg.289-297.
7.31st Session of the Codex Alimentarius Commission (2008),ISN No.418
http://www.codexalimentarius.net/gsfaonline/additives/details.html?id=6
8.Japan’s Specifications and Standards for Food Additives(7th Edition), The Ministry of Health and Welfare,2000,Monograph D177
http://www.ffcr.or.jp/zaidan/FFCRHOME.nsf/pages/spec.stand.fa-c-monographs
9.Summary of Evaluations Performed by the Joint FAO/WHO Expert Committee on Food Additives
http://jecfa.ilsi.org/evaluation.cfm?chemical=GELLAN%20GUM&keyword=GELLAN%20GUM
10. “明胶空心胶囊”,中国药典,第Ⅱ部,438-439
11. 杨会英,吴朝阳等. 羟丙甲纤维素空心胶囊对药物溶出的影响. 药物分析杂志 2004,24(6):651-652
12. 孙欣,陈西广. 保持益生菌食品中益生菌活性的技术方法. 食品工业科技. 2007,28(9):232-235
13.Ewart T. Cole, Robert A. Scott, etc. Enteric coated HPMC capsules designed to achieve intestinal targeting. International Journal of Pharmaceutics. 231(2002):83-95