Creating PVA copolymer capsules

When drugs are encapsulated, electrification (the electrostatic charge of the capsule) may sometimes cause problems, such as capsule adhesion during transportation or dispersion of the capsule content in the filling process. In this article, the electrification of gelatin and nongelatin capsules is examined.

Polyvinyl alcohol (PVA) copolymer capsules are a form of nongelatin capsule under development. PVA, acrylic acid (AA) and methyl methacrylate (MMA) are used as raw materials. As previously reported, these capsules have advantages, such as low gas permeability, and can be particularly suitable for encapsulation of hydrophilic solvents, such as polyethylene glycol (PEG) 400, and surfactants.^1–5 Using such capsules facilitates the formulation of insoluble drugs and is expected to enhance bioavailability.

The electrostatic characteristics of PVA copolymer capsules were determined using gelatin and nongelatin (hypromellose (HPMC)) capsules as controls. After, the stability of a PVA copolymer capsule preparation of indomethacin (IND) solution was examined as a model of an insoluble drug preparation. In addition, the bioavailability of a sparingly water-soluble drug, acetaminophen, and a practically water-insoluble drug, nifedipin (NF), in both gelatin and nongelatin capsules was evaluated by administering the preparations to Beagle dogs.

Key points

Electrostatic characteristics⁶

It is well known that electrification of capsules has different characteristics depending on the raw material of the polymer compound used. Low electrification is desirable and there have been many cases where an antistatic agent was used to reduce capsule electrification. The electrostatic characteristics of three types of capsules were determined.

Measurement of electrification using the Faraday cage method. Approximately 2–3 g of each capsule type was measured out and placed in a Faraday cage (Advantest; Tokyo, Japan). The amount of triboelectricity generated by the capsules was measured with a digital multimeter (Advantest) and the specific charge electrification (nC/g) was calculated (Table 1). Of the three capsule types, the gelatin and HPMC capsules showed high electrification values with positive electricity. In contrast, the PVA copolymer capsule had the lowest electrification value with negative electricity.

Table 1: Specific charges for the three capsule types per 1 g.

Measurement of surface potential charges after generation of triboelectricity. Approximately 10 g of each capsule type was measured out, placed in a tablet friability tester. (Tsutsui Rikagaku Kikai; Tokyo, Japan). Triboelectricity was generated for 1 min and the surface potential charges of 20 randomly selected capsules were then measured using a surface charge electrometer (Model 1279, Monroe Electronics; NY, NY, USA) 5 and 10 min after the start of the test (Figure 1).

Figure 1: Surface potential charge for the three capsule types.

The gelatin capsules gained the most charge and were characterized by positive electrification. Additionally, their surface potential did not decrease easily. HPMC capsules are known to have less water content (~3%) than gelatin capsules (~15%) and their electrification tends to be lower. This tendency was confirmed in these experiments. However, the HPMC capsules showed a high level of surface potential, even after 10 min, and the charge tended not to attenuate easily. This phenomenon is considered to be a result of the low moisture content of the capsules.

The PVA copolymer capsules displayed the lowest level of electrification, as well as a negative charge. After displaying a surface potential charge of ~ –500 V immediately after electrification, the capsules attenuated toward 0 V, proving that these capsules are characterized by easy attenuation of the surface potential charge.

The attenuation of the surface potential charge of the capsules was affected by the functional groups of the raw materials and their polymeric structure. The PVA copolymer capsules are not easily electrified and show easy attenuation of any electricity that is generated.

Stability testing

In contrast with gelatin and HPMC capsules, it has been proven that PVA copolymer capsules are compatible with PEG 400, Tween 80 and LABRASOL.^1–3 In a further experiment, the stability of a liquid preparation of insoluble PEG 400 encapsulated in PVA copolymer capsules was evaluated.

Sample. A PVA capsule of size 0 was filled with 625 mg of PEG 400 solution containing 25 mg of IND and band-sealed.

Stability. The encapsulated sample was placed in an airtight Lamizip AL (Seisannipponsha Ltd; Japan), a heat-shielded PET/AL/PE multilayer film bag, and an accelerated stability test was performed at 40 °C and 75% relative humidity. No appearance changes, leaks or softening were observed after 1, 2 and 3 months of storage. The encapsulated solution was collected from the capsule and its water content was measured according to the Karl Fischer's method. It increased only slightly on storage, but this did not influence the drug dissolution rate (Figure 2).

Figure 2: Change in water content of the encapsulated solution.

Dissolution test. The dissolution testing of the capsule preparation was conducted using Japanese Pharmacopoeia (JP) Apparatus 2 (Toyama Sangyo Co., Ltd; Osaka, Japan [paddles]) at 50 rpm in water and two test solutions (first and second fluids for the dissolution test of JP). IND concentration was assayed using ultraviolet (UV) absorbance at 320 nm. Figure 3 shows that IND dissolved quickly in water and in the second fluid. The dissolution rate for all of the capsule preparations at 15 min was ~100%. However, in the first fluid only 90% of the drug was released. This is considered to be a result of decreased solubility of IND in acid. No effect of storage on drug dissolution was found in any of the fluids.

Figure 3: IND release rate from a solution filled into a PVA copolymer capsule.

Administration of an encapsulated powder form of a water-soluble drug⁷

Sample. Size 1 gelatin, HPMC and PVA copolymer capsules were filled with 250 mg of a mixture containing 150 mg of lactose powder mixed with 100 mg of AA.

Dissolution test. The drug dissolution testing of each capsule was evaluated according to the Guideline for Bioequivalence Studies of Generic Products⁸ using the JP Apparatus 2 (paddles) at 50 rpm in water, 25% McIlvaine buffer solution (pH 5.5, 6.5) and two test solutions (the first and second fluids for the dissolution test of JP). The AA concentration in the fluids for the dissolution test of JP was assayed using UV absorbance at 245 nm.

Figure 4: AA release rate from a capsule preparation in various test solutions.

AA encapsulated in the gelatin, HPMC and PVA copolymer capsules dissolved quickly in the dissolution test solutions. In addition, as the difference in the dissolution rates after 15 min was within ±10% among all the capsules, they were deemed to be equivalent (Figure 4 and Table 2).

Table 2: AA release rate* from a capsule preparation in various test solutions (%).

Animal studies. Animal studies were performed using Beagle dogs (6 dogs; all male; aged 1–2 years; weight 10–11 kg; the same individual used in all tests) with a drug-free period of <1 week between tests.

The capsules were administered orally under fasting and nonfasting conditions, and AA concentration in plasma was assayed by HPLC — as reported previously — before and after 0.25, 0.5, 1.0, 1.5, 2, 3, 4 and 6 h after administration.⁹ The AA plasma concentration profile is shown in Figure 5.

Figure 5: AA blood concentration curve upon administration of the three capsule types filled with 100 mg AA to Beagle dogs (n=56).

C_max (maximum drug concentration) and T_max (time to the maximum drug concentration) were measured from AA plasma concentration data and the area under the curve (AUC) was calculated according to the trapezoid method. The difference among the preparations on each parameter was evaluated by the paired t-test (Table 3). There was no significant difference (p>0.05) between the capsules in each pharmacokinetic (PK) parameter, and the gelatin and nongelatin capsules filled with AA, which was used as a model of a water-soluble drug, were deemed to be biologically equivalent.

Table 3: PK parameters upon administration of the three capsule types filled with 100 mg AA to Beagle dogs (n=56).

Administration of an encapsulated insoluble drug formulation¹⁰

Sample. 100 mg of a 150 mg mixture containing 140 mg of lactose mixed with 10 mg of NF was placed in a size 1 gelatin capsule and used for the dissolution test. In animal studies, a capsule filled with 150 mg of mixture containing 120 mg of lactose mixed with 30 mg of NF was used to ensure adequate absorption. In addition, 0.5 mL of a PEG 400 solution containing 10 mg NF was encapsulated in a PVA copolymer capsule to form a band-sealed liquid formulation.

Dissolution test. Drug dissolubility from the three capsule preparations was evaluated using JP Apparatus 2 (paddles) at 50 rpm in water and the first fluid for the dissolution test of JP. The NF concentration in the fluid for the dissolution test of JP was assayed using UV absorbance at 238 nm.

The dissolution profile is shown in Figure 6. Dissolution of NF from the PVA copolymer capsule filled with NF/PEG solution in the first fluid and in water was ~100% after 15 min, similar to the drug dissolution rate without a capsule. Conversely, the dissolution of NF from the gelatin capsule filled with powder was significantly delayed (<40% in 45 min).

Figure 6: Drug release from preparations containing NF 10 mg.

Animal studies. A solution containing 10 mg of NF, a PVA copolymer capsule preparation of the solution containing of 10 mg of NF, and a gelatin capsule preparation of the powder containing 30 mg of NF were administered orally to fasting Beagle dogs. The NF concentration in plasma, as reported previously, was determined before and after 0.5, 1.0, 2.0, 3.0, 4.0, 6.0 and 8.0 h after administration and was assayed using HPLC-ECD.¹¹ The solution was administered directly to the stomach via a catheter.

The NF plasma concentration profile is shown in Figure 7 and the PK parameters are shown in Table 4. There were no significant differences in PK parameters between the encapsulated and non-encapsulated solutions (p>0.05). In addition, when the solution preparation and the powder preparation were compared taking the difference in NF doses into consideration, the former was found to be improved approximately 6-fold in terms of C_max and approximately 3-fold regarding AUC.

Conclusion

In terms of bioavailability, PVA copolymer and HPMC capsules should be treated as equivalent to the widely used gelatin capsules (Figure 5 and Table 3). In addition, PVA copolymer capsules enable encapsulation of hydrophilic solvent, which makes insoluble drugs dissolve, formulations (Figure 7 and Table 4). These solution preparations were confirmed to enhance bioavailability when administered to Beagle dogs.

Figure 7: NF blood concentration curve after administration of the NF preparations to Beagle dogs (n=56).

PVA copolymer, which is a new pharmaceutical agent, completed safety studies based on the relevant guidelines and was registered in the FDA Drug Master File in 2006.

Table 4: PK parameters upon administration of the NF preparations to Beagle dogs (n=56).

These PVA copolymer capsules have various advantages compared with traditional gelatin capsules, such as low water content, low electrification level and the capability of filling with hydrophilic solvent, and are expected to facilitate the development of new drug formulations in the future.

Noboru Hoshi† was Manager of Technological Research at the Research & Development Group, Nisshin Kasei Co., Ltd (Japan).

Akane Kida is a reseacher at the Research & Development Group, Nisshin Kasei Co., Ltd (Japan).

Takashi Hayashi is Head of Oral Solid Formulation at CMC Development Laboratories, Shionogi & Co., Ltd (Japan).

Yuki Murakami is Scientist, Oral Solid Formulation at CMC Development Laboratories, Shionogi & Co., Ltd (Japan).

References

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7. Y. Murakami et al., "Abstract of the 126th Symposium of the Pharmaceutical Society of Japan," (Sendai, Japan, 2006) p 140.

8. Guideline for Bioequivalence Studies of Generic Products (1997). www.nihs.go.jp/drug/be-guide(e)/Generic/be97E.pdf

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