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The bioavailability of some insoluble drugs is enhanced when they are dissolved in the solubilizing agent macrogol 400, although conventional hard capsules cannot tolerate the agent. This article investigates a PVA copolymer, which has been developed by the authors, examining its properties and its suitability as a material in capsule formulations.
Image courtesy of author.
Hard capsules have been developed as an edible container to mask the taste and odour of medicines. Traditionally used for powder or granulated formulations, capsules have also been adapted to contain oily liquids, tablets and even powders for inhalation. They are popular because of their relative ease of manufacture (compared with other dosage forms such as tablets) and their flexibility to accommodate a range of fill weights. Additionally, capsules readily demonstrate bioequivalence between different strengths of the same formulation.
The solubility of many compounds used in potential new drugs is very low because they are selected for their affinity to receptors, which increases as the lipophilicity of a compound increases. Although these compounds are expected to have a high clinical performance, they often fail to become new drug entities because of their low absorption in the gastro-intestinal (GI) tract - a result of poor dissolution.
The authors developed polyvinyl alcohol (PVA) acrylic acid methyl methacrylate polymer (PVA copolymer) capsules following research indicating that the bioavailability of some insoluble drugs was enhanced when dissolved in macrogol 400 (polyethyleneglycol [PEG] 400), but conventional hard capsules could not tolerate macrogol 400. An earlier study reported that the solubility of a drug in macrogol 400 is approximately 100 times higher than in water (Table I).1 When the drug/water mixture was administered in a suspension to dogs, only 2.2% of the dose was absorbed, but when administered in a solution of macrogol 400, absorption was 91%.
Table I: Solubility of insoluble drugs in macrogol 400 and PK parameters after administration in dogs.
This suggests that pharmaceutical manufacturers could develop dosage forms of insoluble drugs with macrogol 400, improving the solubility of such entities. Because the formulations and manufacturing processes are simple, no scale-up studies would be required - possibly reducing drug development times.
Because of the large potential of capsules that can hold macrogol 400, the authors developed new capsules, synthesizing materials that are suitable as capsule shells. By copolymerizing acrylic acid (AA) and methyl methacrylate (MMA) on PVA as a skeleton and then using the obtained PVA copolymer as capsule shells, the authors successfully developed capsules that can be filled with macrogol 400.2,3 In this paper, the physical properties of the PVA copolymer, and the characteristics and pharmaceutical applications of PVA copolymer capsules, are investigated.
Initially, the authors examined why conventional capsule shells do not tolerate macrogol 400. When gelatin capsules were filled with macrogol 400, they became brittle and broke easily because the moisture in the shell was absorbed by the macrogol. When hydroxypropyl methylcellulose (HPMC) capsules were filled with macrogol 400, the agent oozed out through the capsule shell.
The authors believed that new synthetic polymers would be more suitable for capsule shell materials rather than natural polymers or polysaccharides. Thus, different polymers were synthesized, using styrene resin, polyurethane, acrylic polymer and chitosan as a skeleton.
PVA copolymer was developed by the authors (Figure 1). Commercially available, partially-saponified PVA was used as the raw material for the skeleton of the copolymer. AA and MMA were emulsion-polymerized onto the PVA skeleton.
Figure 1: Typical synthesis of PVA copolymer.
Dissolution of PVA copolymer. Capsules made only of PVA are available, although they are easily softened by surrounding moisture. In the PVA copolymer, MMA was used to increase the hardness of the capsule shell; however, increasing the amount of MMA decreases the polymer solubility. Thus, AA was copolymerized to increase the solubility at neutral pH. The composition ratios of PVA, AA and MMA in the PVA copolymer can be modified; the best copolymer is formed when the levels of PVA, AA and MMA are 70–80%, 2.5–5.0% and 15–25%, respectively.
Drug capsules should dissolve in purified water, as well as in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 6.8) of the disintegration test method listed in the Japanese Pharmacopoeia (JP). The dissolution of PVA copolymer cast film in the above media was examined. The result showed that the film was soluble in all three fluids, indicating that the copolymer has suitable dissolution characteristics. The film showed no erosion, swelling or dissolution in macrogol 400.
Film strength. PVA copolymer film was formed in 100 μm thickness using the casting method. The breaking strength and elongation rate of 40310 mm film segments were examined (Table II), which showed the breaking strength of the PVA copolymer film to be 32.2 N/mm2. The value was slightly lower than that of gelatin film (55.8 N/mm2), but comparable to that of HPMC film (30.8 N/mm2); therefore, the PVA copolymer film was considered acceptable for practical use.
Table II: Tensile strength of films and Table III: Gas permeability through films.
When the PVA copolymer film was moistened in a chamber (25 Â°C/75% relative humidity [RH]), its strength decreased by approximately 25%. Gelatin and HPMC specimens showed larger reductions (more than 50%) in strength when moistened at the same condition.
Although the gelatin and HPMC films showed a low elongation rate before and after moistening, the PVA copolymer film showed a markedly higher rate before and particularly after moistening (312% of the original rate).
Gas permeability of the film. The 100 μm thick film was also used to examine gas permeability by the American Society for Testing and Materials (ASTM) method. Water vapour permeability through PVA copolymer film at 25 Â°C/90% RH was 323.2 g/m2/24 h, which was between the values of the gelatin and HPMC films (Table III). There was no marked difference in water vapour permeability between the three films. In contrast, oxygen permeability through PVA copolymer was significantly less than through gelatin and HPMC films, indicating that it should be impermeable to the PVA copolymer film.
Moisture absorption and desorption isotherm. Generally, water-soluble polymers start to absorb moisture when relative moisture increases by more than 70% and the absorption rate dramatically increases when relative moisture exceeds 80%. The moisture absorption isotherm curve of PVA copolymer is similar to that of gelatin (Figure 2). The moisture desorption of PVA copolymer is similar to its absorption isotherm curve, whereas, for gelatin film, the desorption rate is slower than its absorption rate.
Figure 2: Isotherms of moisture absorption and desorption at 25ÃÂ°C.
Safety study. The authors developed hard capsules using the copolymer based on the properties described earlier. Because the PVA copolymer is a new additive, it is necessary to examine its safety. Recently, the number of newly developed additives has decreased because testing their safety is too expensive. In this case, Huntingdon Life Sciences (UK) performed the safety testing. A single administration test in rats; a micronucleus study in mice; an Ames test; a human lymphocyte chromosome aberration study; a single administration study in dogs; and a maximum tolerated dose (MTD) toxicity study were completed, all indicating no safety concerns. The single administration study in rats showed that the oral lethal dose was more than 2000 mg/kg.
No significant changes in autopsy, pathological or pharmacological findings were observed when the copolymer was administered continuously for 14 days at a dose of 500 mg/kg in dogs. Studies of the absorption, distribution, metabolism and excretion of 14C-labelled PVA copolymer are currently under way. After these are completed, a preliminary long-term oral administration study and a subacute study of the repeated administration for 3–6 months will be performed in rats.
PVA copolymer capsules were prepared by the dipping and forming method. Carrageenan (0.05-0.5%) was added as a gelling agent and potassium chloride (0.05-0.5%) was added as a gelling promoter. This method requires no additional investment for capsule manufacturers because conventional gelatin capsule manufacturing machines can be used. Prototype PVA copolymer capsules were coloured, showed a good gloss and were not different from conventional capsules.
Disintegration and dissolution. Prototype PVA copolymer capsules (size #0) were filled with macrogol 400 and the time taken for the contents to begin to leak out was measured (Table IV). The capsules were filled with the disintegrant croscarmellose sodium and the paddle method (50 rpm) was used to measure the disintegration time as an index of the start of dissolution. The capsules opened in less than 10 min in all the media.
Table IV: Disintegration test and lag time in dissolution test of PVA copolymer capsules.
Capsule hardness . The relationships between the brittleness and moisture content of PVA copolymer, gelatin and HPMC capsules were compared using a hardness tester (Shionogi Qualicaps, Japan). A 50 g weight was dropped at a height of 10 cm onto a capsule and the percentage of broken capsule was determined (Figure 3). At a water content of 8%, the gelatin capsules became brittle and the percentage of broken capsules was 100%. The HPMC capsules did not break, even at 1% water content. PVA copolymer capsules became brittle when water content was less than 4%, but were less brittle compared with gelatin capsules. PVA copolymer capsules did not become brittle or break easily, even when filled with macrogol 400 (which absorbs moisture from the capsule shell) or silica gel grains (desiccant). The authors concluded that these test conditions were too severe to estimate capsule brittleness.
To evaluate capsule deformation, the load required to deform each capsule by 50% was measured using a load cell (Figure 4). The results illustrate that PVA copolymer capsules can be deformed by moisture absorption, but this can be prevented by controlling the water content of the filling and the humidity of the environment, or with moisture-proof packaging.
Figure 3: Brittleness of capsules at different water content and Figure 4: Load required to deform 50% of capsules at different water content.
Filling dissolution. When dissolution testing PVA copolymer capsules (size #2) filled with macrogol 400, the bottom of the capsules quickly dissolved (2 min) in purified water, JP 1st fluid (pH 1.2) and JP 2nd fluid (pH 6.8), with the macrogol 400 leaking out from the bottom.
Two sets of capsules for the insoluble drugs tolbutamide and indomethacin were prepared. One capsule was filled with the drug as a solution of macrogol 400 and the other was filled with a mixture of the drug, lactose (as a filler) and croscarmellose sodium (as a disintegrant). The dissolution behaviour of the capsules was compared using the JP paddle method (50 rpm). The tolbutamide/macrogol 400 capsules almost dissolved completely in 10 min in all the test solutions. However, for the capsules filled with the drug, filler and disintegrant, only 80% of the drug had dissolved after 60 min (Figure 5).
Figure 5: Improvement of tolbutamide capsule (size #2) dissolution when filled with macrogol 400 and Figure 6: Improvement of indomethacin capsule (size #2) dissolution when filled with macrogol 400.
Indomethacin in macrogol 400 solution quickly dissolved in all of the three test fluids, as observed with tolbutamide (Figure 6). However, the dissolution rate of indomethacin with filler and disintegrant was slow, particularly in JP 1st fluid where the solubility was low and the dissolved percentage at 60 min was approximately 20%.
Based on the above data, the dissolution of encapsulated insoluble drugs can be improved when they are dissolved in a solution of macrogol 400.
Absorption of indomethacin in rats. Indomethacin PVA copolymer capsules were prepared using either a solution of macrogol 400 or a mixed powder formulated with lactose and croscarmellose sodium. Both sets were filled into mini-capsules (size #9) and administered to rats to compare the plasma profiles of the drug (Figure 7).4 The results illustrate that between 180-360 min, the capsule containing the drug as a solution of macrogol 400 demonstrated a higher plasma concentration (8 μg/mL) compared with the capsules containing the mixed powder (1 μg/mL). The data suggest that PVA copolymer capsules filled with macrogol 400 improve the bioavailability of insoluble drugs.
Figure 7: Indomethacin absorption improvement after administration of macrogol solution to rats and Figure 8: Stability of PVA copolymer capsules.
Tolerance of PVA copolymer capsules. The solubilizing agents macrogol 400, Tween 80 and Labrasol were filled into PVA copolymer capsules and stored in accelerating conditions (40 Â°C/75% RH) in a sealed container to examine the tolerance of the capsules to the agents. The capsules showed no change in appearance after 6 months (Figure 8).
When a solubilizing agent with a high water content is filled into a capsule, the moisture causes the capsule shell to soften and/or deform. This can be prevented by controlling the water content of the agent and the humidity of the manufacturing environment, and by using moisture-proof packaging, as done for conventional capsules.
Comparison with conventional capsules. Current commercially available hard capsules are made of gelatin or HPMC. Table V lists the advantages and disadvantages of PVA copolymer capsules compared with these capsules. PVA copolymer capsules have similar advantages to HPMC capsules because both have been developed to overcome the drawbacks of gelatin capsules. The advantages of PVA copolymer capsules include no animal-derived material, a low water content, no Maillard reaction and a low electrostatic propensity. Additionally, PVA copolymer capsules demonstrate the unique properties of having very low oxygen permeability and the ability to contain macrogol 400.
A recent report suggests that the successful development of one or two new drugs requires approximately 100 discovery projects and initial in vitro screening of approximately 7 million compounds.
After in vitro screening, pharmacological and preclinical safety studies are performed followed by clinical studies to confirm the efficacy and safety of the drugs in humans before being marketed.
The development of high throughput screening and information technology are making the selection of candidate compounds at the initial screening stage extremely efficient. However, subsequent research still requires trial and error experiments; when compounds are extremely insoluble or unstable, a large number of such experiments are necessary that may lengthen the drug development time and increase the costs.
Figure 9 shows how PVA copolymer capsules can help develop insoluble drugs. With capsule drug development, the formulation should remain constant between preclinical and Phase IV studies. This avoids issues with changing bioequivalence because of formulation changes and scale-up. Additionally, it may be easier to develop a formulation having a high bioavailability. PVA copolymer capsules, therefore, are favourable for the quick and low cost development of insoluble drugs.
Figure 9: Efficient development of insoluble drugs with solution-filled capsules.
PVA copolymer does not have chemically active groups such as those in gelatin and it is more tolerable to different agents than gelatin and HPMC capsules. Before PVA copolymer can be used in marketed drugs, further safety studies are required and the authors anticipate that this will take a further 2 years.
Patents of the capsule have already been filed and the authors plan to supply PVA copolymer capsules globally.6,7 The authors also intend to develop equipment that will give the capsules a protective oxygen barrier.
It is said that more than 200 billion capsules are currently used globally. More than 100 years have passed since gelatin capsules were first developed. HPMC capsules were developed at the end of the 20th century,8,9 and the authors hope that PVA copolymer capsules will help drug development in the 21st century.
Table V: Comparison of capsule characteristics.
1. R. Ibuki, "Approaches to Improve Solubility of Insoluble drugs," Abstracts of Symposium on Formulation Designing for Poorly Soluble Drugs (Kyoto, Japan, 2000) pp 13–16.
2. N. Hoshi, "Development of Polyvinyl Alcohol Copolymer Capsules," Abstracts of 19th Symposium on Particulate Preparations and Designing (Hakata, Japan, 2002) pp 162–167.
3. N. Hoshi et al., "Development of PVA Copolymer Capsules," Pharm. Technol. Japan 19(1), 17–30 (2003).
4. K. Danjo et al., personal communication.
5. N. Hashimoto, "Evaluation of Physicochemical Exploratory Research of New Drugs," Abstracts of 11th Symposium on Formulation Designing of Solid Dosage Form (Osaka, Japan, 2001) pp 39–46.
6. T. Shimamoto, S. Sugiyama and N. Hoshi, PCT-application PCT/WO02/18494 (2002).
7. N. Hoshi, T. Shimamoto and S. Sugiyama, PCT-application PCT/WO02/17848 (2002).
8. S. Matsuura and T. Yamamoto, "New Hard Gelatin Capsules Prepared from Water-Soluble Cellulose Derivative," Yakuzaigaku 53(2), 135–140 (1993).
9. T. Ogura, Y. Furuya and S. Matsuura, "HPMC Capsules - An Alternative to Gelatin," Pharm. Technol. Eur. 10(11), 32–42 (1998).