Properties and application of hydroxypropyl methyl cellulose (HPMC) hollow capsules

Issuing time:2019-06-03 11:34

In addition, with the increase of capsule varieties, the diversity of contents gradually makes people realize that there are compatibility problems between gelatin hollow capsules and some special contents.For example, linking of gelatins by linking contents containing aldehyde groups or by reaction to generate aldehyde groups under certain conditions may result in cross-linking of gelatins.A reductive substance may have a Mailard Reaction with gelatin.Moisture absorption of strong content will make the capsule shell loss of water, lose the original toughness.The stability of the gelatin hollow capsules mentioned above makes the development of the new capsule material more concerned.

What plant-based materials are suitable for the production of hollow hard capsules?Many attempts have been made.China patent document application no. 200810061238.200510013285.3 apply for using starch or starch composition as main capsule material;Wang GM[1] reported that hollow capsules were made from chitosan capsules.Zhang xiaoju et al. [2] reported that konjac - soybean protein was the main capsule material.Of course, the most studied are cellulose materials.Among them, hydroxypropyl methyl cellulose (HPMC) manufacture of hollow capsules has formed a large-scale production.

HPMC is widely used in the field of food and drugs, is a common medicinal excipients, the pharmacopoeia of all countries have collected;FDA and eu approve HPMC as a direct or indirect food additive;GRAS is generally accepted as safe, No. GRN 000213;INS No.464, uploaded in JECFA database, does not limit the daily dose limit of HPMC;In 1997, the ministry of health of China approved it as a food additive, thickener (no. 20), suitable for all kinds of food and added according to production requirements [2-9].Due to the difference in properties between HPMC and gelatin, the prescription of HPMC hollow capsules is complicated, and some gelling agents need to be added, such as gum Arabic, carrageenan (seaweed glue), starch, etc.

HPMC hollow capsule is a product with a natural concept, its material and production process is recognized by the jewish, islamic and vegetarian associations, can meet the needs of people of various religions and eating habits, with 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].No matter in the hollow capsule production, transportation, use and preservation process should control the temperature and humidity of the environment in an appropriate range.The appropriate temperature is 15-25℃, the relative humidity is 35%-65%, so as to maintain the long-term performance of the product.The water content of HPMC film is very low, generally 4%-5%, and about 60% lower than that of gelatin hollow capsules (Fig. 1).During long-term storage, the moisture content of HPMC hollow capsules in the prescribed packaging will be increased, but not more than 9% within 5 years.

Fig1. LOD comparison of HMPC and Gelatin shells under marketers in RH

The low water content makes the HPMC hollow capsule suitable for the filling of hygroscopic or water-sensitive contents to extend the shelf life of the product.

A 2005 study by DSM nutrition company compared the effects of HPMC hollow capsules (Vcaps®) and gelatin hollow capsules on the stability of probiotics (Lafti® l-10 lactobacillus acidophilus).Probiotics are a group of living microorganisms that are taken orally in sufficient quantities to improve the balance of intestinal microbes in the host and to treat intestinal diseases.However, probiotics are very sensitive to water, too much water will lead to the death of live bacteria [12].DSM filled Lafti® l-10 and auxiliary materials with HPMC capsules and gelatin hollow capsules at different humidity, and investigated their stability.The results showed that compared with gelatin hollow capsules, HPMC hollow capsules could better maintain the number of live bacteria in the product and extend the validity period of probiotics products (Fig. 2).

Fig2. Stability comparison of HPMC and gelatin shells in probiotic products

High toughness, no brittle

As mentioned above, the gelatin film has a specified moisture content, if below this limit, the gelatin film will occur significantly brittle.Hollow gelatin capsules without any additives have more than a 10% brittle risk when the water content is 10%.When water continues to drop to 5%, 100% brittle appears.In contrast, HPMC hollow capsules have much better toughness and maintain good performance even when the ambient humidity is low (Fig 3).Of course, the brittle rate of HPMC hollow capsules under low humidity varies greatly among different prescriptions.

Fig3. Flexibility at different moisture level


In contrast, when gelatin capsules are hollow and exposed to high humidity, the shells absorb water and soften, deform, and even collapse.HPMC hollow capsules can maintain good shape and performance even under high humidity conditions.Therefore, HPMC hollow capsule has a strong adaptability to the environment. When the sales area of the product covers a variety of climatic zones or the storage conditions are relatively poor, this advantage of HMPC hollow capsule is particularly significant.

Chemical stability

The crosslinking reaction of gelatin capsules is a difficult problem for capsule preparation.Because the aldehyde group of the contents reacts with the amino group of the amino acids in the gelatin to form a network structure, the capsule shell is difficult to dissolve under the dissolution condition in vitro, thus affecting the release of drugs.Hydroxypropylmethylcellulose is a cellulose derivative with excellent compatibility with most substances due to its chemical inertia. Therefore, HPMC hollow capsules have no risk of cross-linking reaction and have high chemical stability (Fig4).

Fig 4. Dissolution comparison of HPMC and Gelatin shells under stressed the conditions


Good coating performance

Enteric capsules are used for drugs that are easily destroyed by gastric acid, irritate gastric mucosa or need targeted administration.The enteric capsule technology is used to coat enteric pellets and capsules.HPMC hollow capsule in the capsule overall coating shows a unique advantage.

The study showed that, due to the rough surface of HPMC hollow capsules (fig.5), the affinity with most enteric coating materials was significantly higher than that of gelatin, and the adhesion speed and uniformity of coating materials were significantly better than that of gelatin, especially the reliability of coating at the junction of body cap was significantly improved.In vitro dissolution test showed that the permeability in the stomach was lower after the coating of HPMC capsule, and it had a good release in the intestinal tract [13].

Fig5. Scanning electron micrographs of the surface of HPMC and gelatin capsules

HPMC hollow capsule

Gelatin hollow capsule


Fig 6.Dissolution of paracetamol from HPMC capsules coated with Eudragit® L30D-55 and Eudragit® FS 30 D. N=3

6.Dissolution of paracetamol from HPMC capsules coated with Eudragit® L30D-55 and Eudragit® FS 30 D. N=3

Properties and application of hydroxypropyl methyl cellulose (HPMC) hollow capsules

By liu yuan in medicine & packaging

In the history of capsule, gelatin has always been the mainstream capsule material due to its extensive sources, stable physical and chemical properties and excellent processing properties.With the increase of people's preference for capsules, hollow capsules are more widely used in food, medicine and health care products.

However, the occurrence and spread of mad cow disease and foot and mouth disease have raised concerns about products of animal origin.The risk of gelatine, which is often made from the bones and skins of cows and pigs, has become a growing concern.In order to reduce the safety risk of hollow capsule materials, experts in the industry continue to research and develop suitable plant-derived capsules.

In addition, with the increase of capsule varieties, the diversity of contents gradually makes people realize that there are compatibility problems between gelatin hollow capsules and some special contents.For example, linking of gelatins by linking contents containing aldehyde groups or by reaction to generate aldehyde groups under certain conditions may result in cross-linking of gelatins.A reductive substance may have a Mailard Reaction with gelatin.Moisture absorption of strong content will make the capsule shell loss of water, lose the original toughness.The stability of the gelatin hollow capsules mentioned above makes the development of the new capsule material more concerned.

What plant-based materials are suitable for the production of hollow hard capsules?Many attempts have been made.China patent document application no. 200810061238.200510013285.3 apply for using starch or starch composition as main capsule material;Wang GM[1] reported that hollow capsules were made from chitosan capsules.Zhang xiaoju et al. [2] reported that konjac - soybean protein was the main capsule material.Of course, the most studied are cellulose materials.Among them, hydroxypropyl methyl cellulose (HPMC) manufacture of hollow capsules has formed a large-scale production.

HPMC is widely used in the field of food and drugs, is a common medicinal excipients, the pharmacopoeia of all countries have collected;FDA and eu approve HPMC as a direct or indirect food additive;GRAS is generally accepted as safe, No. GRN 000213;INS No.464, uploaded in JECFA database, does not limit the daily dose limit of HPMC;In 1997, the ministry of health of China approved it as a food additive, thickener (no. 20), suitable for all kinds of food and added according to production requirements [2-9].Due to the difference in properties between HPMC and gelatin, the prescription of HPMC hollow capsules is complicated, and some gelling agents need to be added, such as gum Arabic, carrageenan (seaweed glue), starch, etc.

HPMC hollow capsule is a product with a natural concept, its material and production process is recognized by the jewish, islamic and vegetarian associations, can meet the needs of people of various religions and eating habits, with 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].No matter in the hollow capsule production, transportation, use and preservation process should control the temperature and humidity of the environment in an appropriate range.The appropriate temperature is 15-25℃, the relative humidity is 35%-65%, so as to maintain the long-term performance of the product.The water content of HPMC film is very low, generally 4%-5%, and about 60% lower than that of gelatin hollow capsules (Fig. 1).During long-term storage, the moisture content of HPMC hollow capsules in the prescribed packaging will be increased, but not more than 9% within 5 years.

Fig1. LOD comparison of HMPC and Gelatin shells under marketers in RH

The low water content makes the HPMC hollow capsule suitable for the filling of hygroscopic or water-sensitive contents to extend the shelf life of the product.

A 2005 study by DSM nutrition company compared the effects of HPMC hollow capsules (Vcaps®) and gelatin hollow capsules on the stability of probiotics (Lafti® l-10 lactobacillus acidophilus).Probiotics are a group of living microorganisms that are taken orally in sufficient quantities to improve the balance of intestinal microbes in the host and to treat intestinal diseases.However, probiotics are very sensitive to water, too much water will lead to the death of live bacteria [12].DSM filled Lafti® l-10 and auxiliary materials with HPMC capsules and gelatin hollow capsules at different humidity, and investigated their stability.The results showed that compared with gelatin hollow capsules, HPMC hollow capsules could better maintain the number of live bacteria in the product and extend the validity period of probiotics products (Fig. 2).

Fig2. Stability comparison of HPMC and gelatin shells in probiotic products

High toughness, no brittle

As mentioned above, the gelatin film has a specified moisture content, if below this limit, the gelatin film will occur significantly brittle.Hollow gelatin capsules without any additives have more than a 10% brittle risk when the water content is 10%.When water continues to drop to 5%, 100% brittle appears.In contrast, HPMC hollow capsules have much better toughness and maintain good performance even when the ambient humidity is low (Fig 3).Of course, the brittle rate of HPMC hollow capsules under low humidity varies greatly among different prescriptions.

Fig3. Flexibility at different moisture level

In contrast, when gelatin capsules are hollow and exposed to high humidity, the shells absorb water and soften, deform, and even collapse.HPMC hollow capsules can maintain good shape and performance even under high humidity conditions.Therefore, HPMC hollow capsule has a strong adaptability to the environment. When the sales area of the product covers a variety of climatic zones or the storage conditions are relatively poor, this advantage of HMPC hollow capsule is particularly significant.

Chemical stability

The crosslinking reaction of gelatin capsules is a difficult problem for capsule preparation.Because the aldehyde group of the contents reacts with the amino group of the amino acids in the gelatin to form a network structure, the capsule shell is difficult to dissolve under the dissolution condition in vitro, thus affecting the release of drugs.Hydroxypropylmethylcellulose is a cellulose derivative with excellent compatibility with most substances due to its chemical inertia. Therefore, HPMC hollow capsules have no risk of cross-linking reaction and have high chemical stability (Fig4).

Fig 4. Dissolution comparison of HPMC and Gelatin shells under stressed the conditions

Good coating performance

Enteric capsules are used for drugs that are easily destroyed by gastric acid, irritate gastric mucosa or need targeted administration.The enteric capsule technology is used to coat enteric pellets and capsules.HPMC hollow capsule in the capsule overall coating shows a unique advantage.

The study showed that, due to the rough surface of HPMC hollow capsules (fig.5), the affinity with most enteric coating materials was significantly higher than that of gelatin, and the adhesion speed and uniformity of coating materials were significantly better than that of gelatin, especially the reliability of coating at the junction of body cap was significantly improved.In vitro dissolution test showed that the permeability in the stomach was lower after the coating of HPMC capsule, and it had a good release in the intestinal tract [13].

Fig5. Scanning electron micrographs of the surface of HPMC and gelatin capsules

HPMC hollow capsule

Gelatin hollow capsule

Crown of paracetamol from HPMC capsules with Eudragit® l30d-55 and Eudragit® FS 30D. N=3

"Language

The characteristics of HPMC hollow capsule make its application field expand continuously.From all-natural products to moisture sensitive or hygroscopic contents, there are now unique applications in dry powder inhalers and enteric coatings.It should be noted that the oxygen permeability of HPMC hollow capsules listed at home and abroad is relatively high, and disintegration is slightly slower than that of gelatin hollow capsules, but the bioavailability in vivo is similar [11], which should be considered in the development.

As we all know, there is 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 plant-based hollow capsule products have been successfully launched.In 1997, Capsugel took the lead in listing HPMC hollow capsule VcapsTM in the United States, providing a new option for oral capsule.At present, the annual sales volume of HPMC hollow capsules has exceeded 20 billion, and the annual growth rate is 25%.


references

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2. Zhang xiaoju, jiang fantang. Study on forming technology of plant hard hollow capsule. Food science and technology. 2008,33 (12) : 60-62

3. Health standard for food additives gb2760-1996, supplemented varieties, ministry of health of China

4.U.S. Food and Drug Administration. CFR 21 172.665.
http://www.access.gpo.gov/nara/cfr/waisidx_08/21cfr172_08.html
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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. "the gelatin hollow capsule", the Chinese pharmacopoeia, the first Ⅱ department, 438-439

11. Yang huiying, wu chaoyang et al. Effects of hydroxypropanol hollow capsule on drug dissolution. Journal of pharmaceutical analysis, 2004,24 (6) : 651-652

Sun xin, Chen xigang. Methods to maintain the activity of probiotics in probiotic foods. Food industry science and technology. 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


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