Capsule Based Devices

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A range of lag-times can be selected, to enable an increased range of temporal targeting from a single capsule device.

Capsules can be coated with a semipermeable or water impervious layer. A semipermeable coat provides the basis for osmotically driven release. The pressure caused by internal swelling forces the capsule open or ruptures the body to deliver drug. A water-impervious, low-density capsule might also float on the gastric contents, prolonging residence time in the GI tract before providing a pulsed release of a drug after a lag-time. A nonfloating device requires a barrier to external fluids for preventing premature release. The capsule cap may be removed by a swelling osmotic action, or a seal may be inserted in the end of the capsule body, being dislodged after a desired lag-time. Examples of capsule devices capable of delivering pulses are indicated below.

9.7.4.1 Pulsincap

Pulsincap (Fig. 9.3) has an outer impermeable capsule body Fig. 9.3 (v), which houses the drug formulation (Fig. 9.3 [iii]). This can be separated from or be mixed with an expulsion excipient layer (Fig. 9.3 [iv]). Sodium bicarbonate/citric acid effervescing mixtures may be used as expulsion agents [82-84].

The Pulsincap device incorporates expanding low-substitute hydroxypropyl cellulose (L-HPC). In a study evaluating the regional GI targeting of dofetilide, the excipient layer contained sucrose as a soluble excipient [85]. Release was controlled by the length of the hydrogel plug (Fig. 9.3 [ii]) [86]. Figure 9.3 illustrates how the plug is removed by expansion on uptake of water during GI tract transit.

The challenging design of the swellable hydrogel plug and complex insertion process led to the exploration of alternative versions of Pulsincap™. A hydroxypro-pylmethyl cellulose (HPMC)/lactose-based erodible tablet was subsequently developed as studies had indicated that lag-time could be more readily controlled by erosion mechanisms, HPMC being readily erodible in GI tract fluids [87].

9.7.4.2 Egalet

This technology comprises an impermeable shell (Fig. 9.4 [iii]) containing a drug core (Fig. 9.4 [ii]) and two erodible outer layers (Fig. 9.4 [i]) at each open end.

The plug swells in water and forms a frustro-conical shape. This pulls itself free of the insoluble body.

i. Soluble cap ii. Hydrogel iii. Drug layer iv. Expulsion excipient v. Impermeable capsule Fig. 9.3 The Pulsincap™ capsule device

The plug swells in water and forms a frustro-conical shape. This pulls itself free of the insoluble body.

Removal of the plug causes rapid expulsion of the contents from the device.

Removal of the plug causes rapid expulsion of the contents from the device.

i. Erodible outer layer ii. Drug containing core iii. Impermeable

On erosion of the outer layer the drug in the core dissolves on exposure to GI tract contents.

In another variant it is possible to include another drug in the erodible outer layer for sustained release followed by pulsed release of a different drug from the inner core.

The Egalet device is potentially susceptible to inconsistent release due to reliance on uniform erosion at its terminal ends. Krogel and Bodmeier evaluated a similarly constructed device and highlighted the issue of asymmetrical erosion [88].

9.7.4.3 Chronset

Wong et al. describe the Chronset technology [89]. This system can deliver drugs in a pulsatile fashion using osmotic pressure generated inside the semipermeable membrane (Fig. 9.5).

Fig. 9.5 The Chronset® device

i. Semi-permeable cap ii. Osmotic core iii. Rigid barrier layer iv. Drug containing compartment v. Insoluble coat on gelatin capsule i. Semi-permeable cap ii. Osmotic core iii. Rigid barrier layer iv. Drug containing compartment v. Insoluble coat on gelatin capsule

Fig. 9.6 The time delayed capsule (TDC)

i. Gelatin cap ii. Erodible tablet (ET)

iii. Drug loaded tablet iv. Expulsion excipient v. Insoluble coated gelatin capsule body

The capsule shell is water-insoluble (Fig. 9.5 [v]) and houses the therapeutic agent and soluble filler(s) (e.g. sucrose, lactose) (Fig. 9.5 [iv]). A rigid barrier on top of the drug-containing contents (Fig. 9.5 [iii]), transfers the driving from osmotic expansion against the capsule shell. Water from the GI tract is absorbed into the osmotic core (Fig. 9.5 [ii]) through the semipermeable cap (Fig. 9.5 [i]), causing expansion of the osmotic core. This subsequent expansion "pushes" against the rigid barrier, causing separation. Continuing expansion of the osmotic core causes the shell and cap to become separated, exposing the drug-containing compartment to the GI fluids and enabling delivery of the contained drug as a "pulse."

9.7.4.4 Time-Delayed Capsule

A time-delayed capsule (TDC) (Fig. 9.6) comprises a capsule body, coated to render insoluble in water and containing a swelling expulsion excipient, a drug-containing tablet and an erodible tablet (ET).

Gastrointestinal (GI) fluids erode the ET (Fig. 9.6 [ii]), while the capsule body contents are protected by the ethyl cellulose coat (Fig. 9.6 [v]). After a lag-time, determined by erosion time of the ET, water enters the capsule, causing rapid swelling of the expulsion excipient (Fig. 9.6 [iv]). This pushes the undissolved drug tablet (Fig. 9.6 [iii]) free of the capsule body followed by disintegration and rapid drug i.

i. Soluble gelatin cap ii. Waxy plug iii. Drug containing layer iv. Osmotic compartment v. Semi-permeable coat on gelatin capsule

release as a "pulse." For esthetic purposes and ease of swallowing a soluble gelatin cap is placed on top of the device (Fig. 9.6 [i]).

9.7.4.5 Programmable Oral Release Time System®

The programmable oral release time (PORT) device (Fig. 9.7) utilizes osmotic pressure to drive drug release in a similar manner to the Chronset technology. However, the body of the capsule is semipermeable to aqueous fluid, contrasting with the impermeable nature of the TDC (Fig. 9.7 [v]). It contains a swellable osmotic component (Fig. 9.7 [iv]) and drug-containing layer (Fig. 9.7 [iii]).

An insoluble wax plug at the top of the capsule body seals the contents (Fig. 9.7 [ii]). As the contents swell, on ingress of water the waxy plug is dislodged and the drug-containing layer (Fig. 9.7 [iii]) is made available for release/ dissolution. A soluble cap seals the device (Fig. 9.7 [i]). Several variables can be manipulated to control release lag-time. e.g. capsule body wall thickness and composition, concentration of the osmotic contents, and the length/composition of the waxy plug.

9.7.4.6 Pressure-Controlled Colon Delivery Capsule

The pressure-controlled colon delivery capsule (PCDC) capsule design (Fig. 9.8) utilizes two coatings and capitalizes on the varying physiological conditions along the GI tract. Configuration is as follows:

• An insoluble coating is present on the inside wall of a standard capsule (Fig. 9.8 [v]).

• The drug-containing core may comprise an oily liquid base (Fig. 9.8 [iv]).

• An insoluble waxy plug seals the top of the insoluble coat (Fig. 9.8 [iii]).

• The capsule containing the oily coated core with the insoluble waxy plug is sealed with a standard cap (Fig. 9.8 [ii]).

• The entire capsule is then enteric coated (Fig. 9.8 [i]) [90].

The outer enteric coat ii.

dissolved on reaching the SI, the gelatin component iii.

iii.

i. Enteric coat ii. Gelatin capsule iii. Waxy plug iv. Oil v. Insoluble coat dissolved on reaching the SI, the gelatin component iv.

quickly dissolved to leave a v.

fragile balloon like ethyl cellulose structure coated i. Enteric coat ii. Gelatin capsule iii. Waxy plug iv. Oil v. Insoluble coat

Once ingested the capsule remains intact at gastric pH. The enteric coat and gelatin dissolve in the intestine, leaving a relatively fragile balloon-like structure that is ruptured by the elevated pressure at the illeo-cecal junction. Drug is accordingly released at colonic entry.

9.7.4.7 Colon-Targeted Delivery Capsule

A schematic of the colon-targeted delivery capsule (CTDC) is shown in Fig. 9.9. It comprises a capsule (Fig. 9.9 [i]) coated with three layers.

The innermost coat comprises an acid soluble layer (Fig. 9.9 [iv]), which in turn is coated with a water soluble layer (Fig. 9.9 [iii]). The outermost coat comprises an enteric polymer (Fig. 9.9 [ii]) that does not dissolve until the capsule device has emptied from the stomach.

The enteric and water-soluble coats dissolve in the small intestine to expose an acid-soluble layer that dissolves in the colon, liberating the contained drug [91].

Fig. 9.8 Structure and function of the PCDC

Fig. 9.9 Structure and function of the CTDC

Colon Drug Delivery

Fig. 9.10 The HS capsule

i. Soluble gelatin outer capsule ii. Soluble gelatin inner capsule iii. Soluble drug containing core iv. Hydrophilic polymer i. Soluble gelatin outer capsule ii. Soluble gelatin inner capsule iii. Soluble drug containing core iv. Hydrophilic polymer

9.7.4.8 Hydrophilic Sandwich Capsule

The hydrophilic sandwich (HS) concept (Fig. 9.10) comprises:

• Two different-sized capsules, one contained within the other [i].

• The void space contains various concentrations of a hydrophilic polymer such as HPMC, creating a hydrophilic "sandwich" [iv].

• A drug-containing core [iii] is housed within the inner capsule [ii].

The outer capsule rapidly dissolves on exposure to an aqueous environment. The hydrophilic "sandwich" then forms a gel barrier, protecting the inner drug layer for a predetermined lag time depending on gel layer thickness and concentration/type of hydrophilic polymer [92].

The capsule-based systems described above have a number of potential disadvantages with respect to consistency of performance. The Chronset, PORT System, and Pulsincap devices all rely on swelling mechanisms that are vulnerable to frictional forces associated with plug removal or other release-determining sequences, e.g.:

• Rugosity of the internal surface of the Pulsincap capsule is not uniform. Thus, frictional forces vary as the hydrogel plug swells, giving variable lagtimes.

• Frictional forces on the external surface of the Chronoset capsule during cap removal can cause variable release times. The rigid barrier layer, which acts as a swelling block, can also restrict drug release from the core.

• The PORT System is subject to the influence of frictional forces as the osmotic core swells to expel the waxy plug. Additional studies have highlighted the importance of a tight fitting seal by using hot-melt wax plugs [93]. These prevented premature drug release.

• The formation of an ethyl cellulose pressure-sensitive balloon structure in the PCDC can also cause variability. Premature bursting may occur due to intersub-ject GI pressure variations. The flexible balloon structure formed after dissolution of the outer coat may also compromise plug fit.

Capsule-based devices are summarized in Table 9.5.

Table 9.5 Capsule-based pulsed delivery devices

Capsule device

Comments

References

Pulsincap™ A water impermeable capsule body consisting with [94]

hydrogel plug. Plug length and insertion depth controls lag-time control (Fig. 9.3) Egalet™ An insoluble tubea with erodible plugs inserted at either [95]

end. Plugs are comprised of selected M PEG, waxy materials and surfactants. Composition controls lag-time (Fig. 9.4)

Chronset® An osmotically coated active compartment within a [89]

semipermeable cap This swells to pushes against a rigid barrier layer and removes the cap. Lag-time is controlled by the osmotic potential (Fig. 9.5) Time-delayed Water impermeable coat on gelatin capsule with an [96-100]

capsule erodible tablet. Erosion of the tablet allows water to enter the capsule, swelling of an expulsion excipient causes expulsion of the drug (Fig. 9.6) Programmable A water-permeable coated gelatin capsule with a [101-103]

Oral Release swellable osmotic core and sealed with an insoluble wax

Time (PORT) plug. The contents swell to remove the plug.

System® The wall thickness and composition, concentration of the osmotic contents and the length of the hydrogel plug control lag-time (Fig. 9.7) Pressure-controlled Internally coated capsule. Drug is filled into the [90, 104, 105]

colon delivery PCDC in an oily liquid base, and sealed with an insoluble capsule (PCDC) waxy plug. Elevated pressure exerted by the ileocaecal junction, ruptures the device to release drug into the colon (Fig. 9.8)

Colon-targeted Enteric outer coat dissolved in the SI to expose an acid [91] delivery capsule soluble layer, which dissolves in the colon (Fig. 9.9) (CTDC)

Hydrophilic HPMC layer sandwiched between a large outer gelatin [91]

sandwich capsule and a smaller inner gelatin capsule-containing capsule drug. Erosion of the HPMC layer provides a lag-time, controlled by grade and/or thickness (Fig. 9.10)

a Capsule shaped

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