1. Introduction

The vacant hypromellose capsules are made from hypromellose and excipients. Hypromellose is 2-hydroxypropyl ether methyl cellulose with a relative molecular weight of 86000. It is derived from cotton linter or wood pulp fiber, which is treated with caustic soda and then etherized with propylene oxide, chlorane and alkali cellulose. Based on the addition of gelling agent, the vacant hypromellose capsules can be divided into two types, one with gelling agent and the other without gelling agent.

Most vacant hypromellose capsule manufacturers add gelling agent (such as carrageenan, gellan gum, sodium alginate, etc.) to hypromellose solution to prepare the vacant capsules, as hypromellose does not have the gelling property. However, the gelling agent is easily affected by pH of the dissolution medium and metal ions. In the simulated dissolution test in vitro, the dissolution rate of capsule shells in different dissolution media slows down, and the dissolution rate of the contents is affected as well. 

The vacant hypromellose capsules without gelling agent can be dissolved quickly in different dissolution media to release drugs. Currently only Vcaps®Plus from Capsugel and H-caps®-Pure from Lefancaps® are available in the market.

2. Advantages

(1) Low water content without brittleness, even with 1% water content. Less influenced by regional environmental deviation. More suitable for hygroscopic and moisture-sensitive drugs or functional food.

(2) The dissolution rate of the capsules without gelling agent is less affected by temperature and pH of the dissolution medium. 

(3) Hypromellose is part of cellulose methyl and polyhydroxypropyl ether with a stable chemical property. No risk of cross-linking and Maillard reactions. No interaction with the contents. Disintegration delay of the vacant hypromellose capsules will not be incurred. The drug release rate is relatively stable. Can be widely used. 

(4) The vacant hypromellose capsules have a small or no electrostatic effect, and a small electrostatic adsorption to the contents, which hence works better for drug filling.

(5) Hypromellose is compatible with most polymer materials. Coating material is easily adhered to the capsule shells with a good uniformity. It can be a water-based coating as well as a coating with ethanol and other organic solvents. Especially suitable for the preparation of those capsules with controlled release coatings.

(6) Low occurrence rate of friability. Strong moisture resistance and good stability. The vacant hypromellose capsules are more suitable for dry powder inhalers from security prospective compared with empty gelatin capsules.  

(7) The vacant hypromellose capsules have a smaller adhesive force on esophagus than empty gelatin capsules. Less adverse reactions such as foreign body sensation. Improved patient compliance.  

(8) Low requirements on storage conditions. Almost non-brittle in low humidity environment, stable in high temperature, and not easily adhered. 

(9) Originated from plants. No risk of animal disease. Can meet the needs of people with special religious beliefs and vegetarians.

3. Dissolution test with Lefancaps® capsules

At present Lefancaps® has two types of vacant hypromellose capsules, H-caps® (with gelling agent) and H-caps®-Pure (without gelling agent). With a dissolution test on these two capsules, the results indicate that the dissolution rate of H-caps® is greatly influenced by pH and metal ions, while H-caps®-Pure is not affected by them.

3.1 Test method

0.25g cefradine powder is respectively filled into empty gelatin capsules, H-caps® (type I and II) and H-caps®-Pure (type III). Based on the requirements of Cefradine capsules from Ch.P 2020, Volume II, the dissolution data of above finished drug capsules in purified water, pH 1.2 hydrochloric acid solution, pH 4.5 potassium dihydrogen phosphate solution and pH 6.0 potassium dihydrogen phosphate solution are tested respectively.

3.2 Result analysis

(1) The dissolution curve of the empty gelatin capsules, H-caps® (type I and II) and H-caps®-Pure (type III) in water medium is shown in the figure below.

(2) The dissolution curve of the empty gelatin capsules, H-caps® (type I and II) and H-caps®-Pure (type III) in pH 1.2 hydrochloric acid solution is shown in the figure below.
(3) The dissolution curve of the empty gelatin capsules, H-caps® (type I and II) and H-caps®-Pure (type III) in pH 4.5 potassium dihydrogen phosphate solution is shown in the figure below.
(4) The dissolution curve of the empty gelatin capsules, H-caps® (type I and II) and H-caps®-Pure (type III) in pH 6.0 potassium dihydrogen phosphate solution is shown in the figure below.
The dissolution test results indicate that the dissolution rate of H-caps® is greatly influenced by pH and metal ions. H-caps®-Pure don’t contain the gelling agent, so they have a similar dissolution curve with empty gelatin capsules. Moreover, the dissolution rate of H-caps®-Pure is not affected by pH or metal ions, and they have a faster release rate in different dissolution media.
H-caps®-Pure show consistent performance under different dissolution conditions and are more suitable to be used for chemical drugs. The drugs in the dosage form of vacant hypromellose capsules without gelling agent in the market all over the world are Dalafenib capsules, Lovastinib capsules, Dabigatrenyl mesylate capsules, Adefovir dipivoxil capsules and etc. A variety of razole products that we are familiar with, such as omeprazole, esomeprazole, dexlansoprazole, rabeprazole and pantoprazole are proton pump inhibitors. In general these drugs have two distinct features, sensitive to moisture and unstable in the acidic condition. Hence, the vacant hypromellose capsules are the best choice for this kind of drugs. Monupivir capsules currently developed by Merck for the treatment of novel coronavirus are also vacant hypromellose capsules without gelling agent.
 
4. Future development tendency
The vacant hypromellose capsules without gelling agent are similar to empty gelatin capsules in terms of solubility, disintegration and bioavailability, and even have the advantages of empty gelatin capsules that don’t have. However, they are not widely used at present. One of the main reasons is higher product price, due to the relatively high raw material cost of hypromellose. Meanwhile, the technology is difficult because of the technical barrier. Very few manufacturers are capable to produce this type of capsules, which hence are limited in the application for pharmaceutical preparation. H-caps® and H-caps®-Pure developed by Lefancaps® can be customized based on the customers’ requirements on capsule dissolution.
The sales of the vacant hypromellose capsules only accounts for about l0% in the international capsule market, but they are expected to gather momentum. With the change of people’s lifestyle and the popularity of Pure & Nature concept, the vacant hypromellose capsules will get more and more attention, and the consumers will tend to pursue green and healthy capsules. They have the potential to replace the empty gelatin capsules and are expected to form a new setup with the empty gelatin capsules for some years to come. Moreover, they have a broad market growth space, more fit for people’s dietary and market needs, and will have a strong development prospect in the field of capsules.