oral modified release delivery technologies(procise and ring cap)

Oral Modified Release Delivery Technologies

ByVishesh Rodrigues 1st Year M.Pharm

Pharmaceutics

1KLEU's College of Pharmacy Belgavi

Introduction

• The oral route of drug delivery is typically considered the preferred and most patient-convenient means of drug administration.

• During drug discovery a lot of effort is put into identifying and orally active candidate that will be reproducible and have effective plasma concentrations in vivo.


• Many orally active compounds are either incompletely or ineffectively absorbed after oral administration (i.e., bioavailability is an issue), or that the required dosing frequency is too short to enable once- or twice-daily administration (i.e., pharmacokinetic half-life is an issue).

• Modified-release formulation technologies offer an effective means to optimize the bioavailability and resulting blood concentration-time profiles of drugs that otherwise suffer from such limitations.


Procise: Drug Delivery SystemsBased on Geometric Configuration

• Procise was developed by Glaxo Canada Inc.1 in 1991.

• Procise is an oral modified-release drug delivery system comprised of a compression-coated core whose geometric configuration controls the release profile of drugs.

• By varying the geometry of the core, the profile of the drug release can be adjusted to follow zero order, first order, or a combination of these orders.

• The system can also be designed to deliver two drugs at the same time, each having a different release profile.

1-Current name and address: Glaxo SmithKline, 7333 Mississauga Road, Mississauga, ON, L5N,6L4, Canada

KLEU's College of Pharmacy Belgavi 4

Description Of The Technology

• The system consists of a core that contains uniformly dispersed drug and has a hole in the middle.

• A slowly permeable inactive coat surrounds all of the surface of the core except the surface of the cylindrical face.

• The drug release occurs only from the cylindrical face, whose surface area dictates the rate of release of drug.


Mechanism of Release

The mechanism of release of drug from this uniquely designed dosage form can be diffusion based or dissolution based.

A. Theory of Procise System Based on Dissolution Mechanism

B. Theory of Procise Based on Diffusion Mechanism


Theory of Procise System Based on Dissolution Mechanism


• The release rate, dm/dt, of a drug from a compressed soluble disc, when governed by dissolution, can be expressed as

dm/dt =A(dx/dt)C

• where A is the surface area, C is the concentration of the drug in the core, and dx/dt is the mass erosion rate. The above equation predicts a constant dissolution rate if the surface area is kept constant, active substance is uniformly distributed within the tablet, and the mass erosion rate is uniform.

Configuration of the zero-order release active core used in Procise: (1) cylindrical face, (2) cylindrical bore, (3) outer wall of cylinder, (4) inert coat. Dt-diameter of the core; Dc-diameter of the cylinder; Ht-thickness at the cylinder; Hp-thickness at the cylindrical face.


Theory of Procise Based on Diffusion Mechanism

• The release of drug from a solid matrix by diffusion can be represented by the following equation:

dq/dt= - D A dc/dr• where q is the mass of drug being transferred, t is the time,

c is the drug concentration, r is the diffusion path length, A is the area for the mass transport, and D is the diffusion coefficient of the drug. According to the above equation, the drug release rate decreases as the diffusion path length, r, increases. As r cannot be kept constant, one way to keep the release rate constant is to increase the area of available diffusion source to compensate for the increase in diffusion distance of drug transport.



Schematic cross-sectional views at various stages of dissolution testing of a Procise formulation designed to release drug at a constant rate: (1) coat, (2) active soluble core, (3) cylindrical face, (4) central pillar attached to the upper and lower face of the coat, (5) core/coat interface. Dt-diameter of the tablet core; Hp-thickness of the cylindrical face.

Manufacturing Process

• Manufacturing processes for the diffusion- and the dissolution-based systems are very similar.

• However, the diffusion-based cores are composed of soluble and insoluble components whereas dissolution-based cores are composed of soluble components only.

• Granules for the cores are prepared using conventional, dry or wet granulation methods and cores are compressed on a conventional press fitted with core-rod punches.

• The precompressed cores are compression-coated using a core coater fitted with a set of specially designed tooling for placing cores precisely in the dyes.


Sequence of compression coating process: (1) coating granules for upper face of the tablet, (2) core, (3) coating granules for lower face of the tablet.


Development And Optimization Of Technology

• During the early development trials, it became clear that erosion of the dissolution cores must occur only from the exposed surface, which is the cylindrical face, and the erosion must be uniform to achieve drug release profiles as per theoretical predictions.


Dissolution profile of Tablet A(Dissolution based procise) and Tablet B(Reformulated Tablet A) in simulated fluid (USP) without enzyme.


NMR images of dissolution-based Procise tablet(Tablet A ) at various stages of dissolution: (A) 15 min, (B) 1 h, (C) 2 h, (D) 3 h, (E) 5 h, (F) 6 h, (G) 7 h, (H) 14 h.


• The hydration of the core for Tablet A is clearly visible in the 15-min image. The sign of hydration of the core also appears at the core coat interface as seen in the 1-h image (B).

• It was observed that the whole core/coat interface on both sides of the tablet had hydrated, suggesting that the penetration of the medium occurred through the coat.

• The coat was reformulated to retard the rate of penetration of the dissolution medium into the coat to prevent hydration of cores from the sides.


NMR images of Tablet B(Reformulated tablet A) at various stages of dissolution: (A) 20 min, (B) 1 h, (C) 2 h, (D) 3 h, (E) 5 h, (F) 7 h, (G) 9 h, (H) 16 h.


• The dissolution plot of Tablet B indicates that the drug release from this tablet with the modified coat formulation was complete in 5h.

• The NMR images of Tablet B showed no sign of water along the core/coat interface throughout the core dissolution process.

• Careful inspection of the images of Tablet B reveals that the water begins to penetrate the coat at some point earlier than 1 h but at a much lower rate than in the case of Tablet A.


In Vitro Studies

• Several in vitro studies have been carried out to demonstrate that the drug release profile from Procise follows the theoretical predictions. Release profiles of two Procise formulations, one based on the dissolution mechanism and the other based on the diffusion mechanism, are shown in the figures below.


Release profile of the dissolution-based Procise formulation of labetalol hydrochloride in water


The plot in Figure shows a zero-order release profile for a dissolution- based Procise formulation of labetalol hydrochloride over a 10-h period.

Release profiles of diffusion based Procise of salbutamol sulfate in water.


The plot in Figure displays dissolution behavior of a diffusion-based Procise formulation of salbutomol sulfate. All of the drug is released in 6.5 h.

In Vivo Studies

• The in vivo drug release behavior of dissolution-based Procise system has been evaluated using a gamma scintigraphy technique in six healthy male subjects.

• Neutron-activated samarium-153 and ytterbium-175 were used to label the core and the coat, respectively, of a placebo tablet.

• The tablet showed no apparent physical changes after neutron bombardment. In vitro core dissolution time of 4.5 h remained unchanged after neutron activation.


Advantage

• Procise has the competitive advantage over other oral delivery systems as the drug release profile can be easily modulated in a predictable manner simply by changing the geometric configuration of its core. No other drug delivery system currently on the market can claim this feature.


Conclusion• A lag time is usually associated with osmotic systems,

coated diffusion matrices, and coated dissolution matrices before the drug is released. There is no lag with Procise systems.

• Salient features of Procise technology:- No intact residue is left in the body as opposed to many

diffusion-based matrices.

Utilization of compression coating process, which does not require solvents.

No fear of dose dumping as the system’s core itself is slow dissolving.

The system can be easily manufactured on a commercial scale.


Ring Cap Technology• RingCap is a patented, oral controlled-release drug delivery system.

The dosage form is a capsule-shaped matrix tablet to which bands of insoluble material are applied circumferentially to the surface of the tablet.

• These bands modify the release of drug from the tablet through the control of surface area

• the release of drug from RingCap tablets is proportional to the surface area exposed to the dissolution media. This surface area changes over time as the area around the bands becomes hydrated and erodes creating new surface area

• This new surface area can decrease, remain constant, or even increase with time. The exposed surface area is controlled by the number, width, and placement of bands of insoluble material applied to the tablets.



RingCap Tablets

Historical Development

• RingCap was developed to address the continuing need for improved oral controlled-release drug delivery systems.

• The intent was to provide a delivery system with reliable and reproducible drug release characteristics, but also a simple and cost-effective system that could be manufactured with conventional solids-processing equipment.


Description of The Technology

• Drug Release:- The RingCap system is based on the principle that the rate at which a drug

is released from an erodible matrix is proportional to the surface area exposed to surrounding liquid over time.

Shown schematically is the release rate of drug from a conventional matrix tablet decreases proportionately over time Fig 1

A typical release profile for acetaminophen formulated in a conventional matrix tablet is shown in Fig 2

The specific configuration of number, width, and placement of the bands on the RingCap tablet determines the release profile. Figure 3 shows the release profile for acetaminophen RingCap tablets with four 2-mm bands.

A proprietary mathematical model, developed to predict the release of drug from RingCap tablets, allows for the design of specific banding configurations that target the desired release profile prior to laboratory experimentation, thereby shortening development time.



Fig 1-Schematic erosion of a conventional matrix tablet.

Fig 2-Release from 750-mg acetaminophen matrix tablets (no bands.)


Schematic erosion of a RingCap tablet.

Fig 3-Release from 750-mg acetaminophen RingCap tablets (four 2-mm bands).

• Formulation and Manufacturing:- RingCap tablets are manufactured using a patented combination of readily

available manufacturing techniques and equipment.

The matrix core tablet can be prepared by multiple techniques such as low- or high-shear wet granulation, fluid-bed granulation, or dry blending.

Capsule-shaped tablets are compressed using high-speed tabletting equipment

A film coat is applied to the matrix tablets to prepare the surface for the application of bands.

The banding material for Ring- Cap tablets is selected from a group of polymers that are insoluble and impermeable. The banding formulation may contain plasticizers, colorants, or other additives depending on the specific application.

Conventional capsule banding equipment (modified to apply multiple bands) is employed to apply the bands around the circumference of the matrix tablets.


Research And Development

• Technical Development:- Acetaminophen was selected as a model drug to challenge various

parameters of the RingCap system, particularly the number, width, and placement of bands on the surface of tablets.

Various band configurations were evaluated for in vitro release using a USP Type III dissolution apparatus.

A comparison of acetaminophen tablets with different numbers and widths of bands indicated that the rate of release and total amount released in 18 h decreased with increasing number of bands and width of bands.

The placement of bands on the surface of acetaminophen tablets also affected the release rate.

A comparison of RingCap tablets with two 5-mm bands separated by either a 1- or 3-mm gap demonstrated that, although the tablets had the same exposed surface area, the tablets had statistically different release profiles.


The combined effect of number, width, and placement of bands was evaluated using two groups of RingCap tablets: tablets with two 4-mm bands and tablets with four 2-mm bands.

The results of this evaluation showed that the percent of acetaminophen released in each hour (over 18 h). Hence it was concluded that the drug release profiles from the RingCap system depend significantly on the specific banding configuration.

The proprietary mathematical model predicts drug release by using the erosion rate of the matrix core tablet and the effect of the various banding parameters, notably the number, width, and placement of bands.

The mathematical model was challenged in numerous studies by comparing the predicted release profilesto the actual in vitro dissolution data. In each case, the profiles were significantly correlated ( p 0.001). Figure 4 shows a representative correlation for 750-mg acetaminophen tablets with two 4-mm bands.



Fig 4-In vitro dissolution versus model predicted for 750-mg acetaminophen Ring- Cap tablets with two 4-mm bands.

• Clinical Studies:- A critical aspect in the development of a novel drug delivery technology is

the demonstration of in vivo performance. For the RingCap system, a randomized, single-dose, three-way, crossover study was conducted in 12 healthy adult human volunteers (eight males, four females) using acetaminophen as a model drug.

Acetaminophen meets the criteria as a highly soluble, highly permeable Class I drug according to the Biopharmaceutics Classification System

The three acetaminophen dosing arms in the study included: a 750-mg RingCap tablet (with two 4-mm bands), a 750-mg unbanded matrix tablet, and a commercially available immediate-release dosage form (two 325-mg tablets). A 1-week washout period was included between doses.

• The results of this human study showed highly significant differences among the three formulations for each of the nine pharmacokinetic parameters examined. A comparison of the fraction released and fraction absorbed for the RingCap tablets indicated a Level A in vitro–in vivo correlation


In addition, the mathematical-model-predicted release of acetaminophen from the RingCap tablets was compared to the in vivo fraction absorbed.

As shown in Figure 3, a significant correlation was demonstrated. This comparison demonstrates that once an in vitro–in vivo correlation is established, the mathematical model can be used to predict in vitro release profiles and the resulting in vivo plasma concentrations.


In vivo mean fraction absorbed versus model predicted release for 750-mg acetaminophen RingCap tablets with two 4-mm bands

Competitive Advantage

• RingCap is differentiated from other oral-controlled release technologies by the availability of a proprietary mathematical model used to predict the release of drug and shorten development time, the use of conventional materials and processes, the relative ease and cost-effectiveness of manufacturing, and the distinctive appearance of the final dosage form.

• The RingCap system uses conventional matrix tablet excipients and formulation. It is adaptable to a wide range of drug concentrations and solubilities. RingCap tablets are manufactured using a patented combination of conventional tablet processing and capsule banding technologies that can be easily integrated into existing manufacturing lines.

• Since there is no need for specialty manufacturing, which often requires outsourcing activities, RingCap offers a cost-effective technology that allows an innovator company to maintain control of quality, cost of goods, and market supply.


References

• Modified-Release Drug Delivery Technology edited by Michael J. Rathbone1,Jonathan Hadgraft2 ,Michael S.Roberts3

1. Inter Ag Hamilton, New Zealand.

2. Medway Sciences, NRI University of Greenwich Chatham, England.

3. Princess Alexandria Hospital and University of Queensland Brisbane, Queensland, Australia.


oral modified release delivery technologies(procise and ring cap)

Health & Medicine

drug release

mechanism of release

rate of release

release rate

drug discovery

dispersed drug

order release active

release prole of drugs