Pharmaceutical Context & Patient Oriented Needs

Skyepharma is providing a number of services to answer the various clients and the different medical needs that are unmet today. Specifically, it is of common knowledge that the pharmaceutical market is continuously evolving and currently moving to the 3rd and/or 4th generations of drugs which are now targeting very unique aspects of each diseases and consequently very specific regions of the GIT (Gastro-Intestinal Tract). Compression of the tablets is an essential phase.

Today, extremely high expectations are arising for combo drug products – combination of APIs in one single drug -, as well as new drug products demonstrating increased bioavailability and/or a reduced number of dose intakes per day; all ultimately participating to a much better benefice/risks ratio for the patient. Moreover, technological answers to the food effect are key for new drug product developments.

To answer each of these challenges, Skyepharma has a number of technologies to propose to its clients. Among those proprietary technologies, two of them are already on the market for more than 20 years. Strongly recognized from the scientific community, Skyepharma’s expertise has demonstrated proven efficiency and efficacy over the years. Those two technologies are the Geomatrix® Technology and the Geoclock® Technology. They both are based on complex tablets compression approaches.

Skyepharma: Expert in Modified Release Drug Development & Commercial Manufacturing

The Geomatrix® and the Geoclock® technologies allow Skyepharma to answer a number of difficulties regarding the complex release profiles expected for the drugs.

Skyepharma can propose and design standard immediate release profile drugs or formulations. Skyepharma’s expert teams we can also provide delayed release profiles and sustained release profiles which are both part of the broad and very diversified family of modified release formulations. These particular drug profiles can be proposed as individual release systems.

They can also be proposed as a combination of two or more release profiles for one or more APIs – to achieve for instance the so called multipulse or chronotherapeutic drug products.

Skyepharma experts can also design drug products with a combination of immediate release and delayed release or an immediate plus a sustained release, also known as the quick-slow release pattern.

The very precise finetuning of the release profiles is key today to answer the specific Target Product Profile (TPP) that are desired by the pharmaceutical companies. To successfully develop and manufacture such high complexity drug products, Skyepharma teams are not only using Skyepharma’s proprietary technologies but they also rely on the long historic and very strong internal expertise in the field of complex tablets compression, and specifically, in multilayers tablets compression and press-coated (or tab-in-tab or dual core) tablets compression.

Geomatrix® multilayers tablets

Geomatrix® is a well-established, validated and customizable oral drug delivery platform technology. Geomatrix tablets are multi-layer tablets usually proposed for drugs which need a sustained release profile formulation.

Geomatrix® can be designed as a bi-layer or a tri-layer tablet. We can vary the tablet geometry and we can adjust the layers’ individual compositions and thickness in order to perfectly match the client’s TPP and, for example, to maintain and control the release of the active ingredient over all the upper gastrointestinal tract – GIT- or the small intestine.

With Geomatrix® tablets, Skyepharma can also combine multiple APIs in one single tablet, and propose different release profiles for the different APIs in the same drug product.

The Geomatrix® technology is present on the EU, US and Brazilian markets, for more than 20 years.

Dissolution profile for immediate and extended release with two APIs – Multi-layer tablet technology Geomatrix®.

With Geomatrix®, the modulation of the drug release profile is achieved by using a multi-layered tablet that combines two key features:

• (i) the use of highly swellable hydrophilic polymers
• (ii) the dynamic control of the surface of the layer containing the drug that is exposed to surrounding fluids.

The combination of layers, each with different rates of swelling, gelling and erosion, controls the drug release rate within the body. When swallowed, the Geomatrix® system limits the amount of drug released by controlling the surface of the drug-containing layer exposed to fluids.

Skyepharma is proud to partnership with HATA.

The Geomatrix® multi-layer tablets require the use of specific press for their manufacturing. Skyepharma production plant has not less than three industrial press able to manufacture this type of complex tablets.

Those industrial press equipment can produce multilayer tablet at high speed, and over 90 000 units per hour. In a popularized way, one can imagine three press combined into a single unique press equipment. The use and more important, the know how to produce tri-layers tablets, controlling sticking between the different layers of the tablet is key!

A large number of parameters related to the powders themselves (physicochemical interactions between three different mixtures) as well as machine control and piloting, are stakeholders into the expertise required to obtain all necessary critical quality attributes, in addition to the release profile expected for the final tablets.

Moreover, all these presses are equipped with online metal check and de-duster systems to ensure multilayers tablets production compliant with the highest quality standards.

Lastly, Skyepharma’s operators and technicians are continuously trained on the press and the production procedures to keep their expertise at top level. Some experts operators are working on these equipment for more than 20 years. They are the perfect trainers for the new comers to whom they provide all know-how and specific operating instructions in duo before they can run a production autonomously.

Geoclock® press-coated tablets

The Geoclock® technology is more specific to the delayed release formulations. Geoclock® is a tab-in-tab – a tablet in a tablet – also known as a press coated tablet or dual core tablets. APIs can be loaded into the core tablet and in the outer layer depending on the targeted release profile.

With Geoclock®, we can offer an API release into the GIT after a precisely controlled number of hours post-intake, independently of GIT pH or meal vincinity. This lag-time can be finetuned between a couple of hours and up to more than 8 to 10 hours.

Geoclock® is of particular interest when you need to have a drug released during the night or when a combination of immediate release and delayed release profiles – like a pulsatile release – is required. This is a very tricky technology that is present on the market since more than 10 years in Europe and in the US.

Dissolution profile for delayed release with two lag time – Press Coated Tablet technology Geoclock®.

Geoclock® is in its simplest form a dry-coated tablet with an active drug core inside an outer tablet layer comprising a mixture of hydrophobic wax and brittle material.

This configuration generates a pH-independent lag-time prior to the release of the active drug. After the pre-defined and configurable lag-time the inner tablet releases the active drug either as a burst or with a controlled release pattern. The controlled release characteristics of the inner core can be modified to achieve the desired profile.

The physiochemical characteristics of the core and the outside tablet layer, can be modified to achieve the desired profile by playing with a large number of parameters like the hydrophobic/hydrophilic balance of the core and layer components or the swelling behavior of the core and the outer layer.

When the production of the cores is based on a standard single-layer tablet compression equipment (like Skyepharma’s Fette 2100 press), a higher complexity in terms of machine is required for the manufacturing process of the final tablet.

The Kilian S250 machine is designed to distribute and center the cores into the outer tablet.

Besides the online metal check and de-duster systems that are present on this press to ensure these complex tablets production at top level quality standards, our press coater is also mounted with a specific online centering check system to control the proper and precise centering of the cores for 100% of the tab-in-tab manufactured.

This specific online centering check is performed using a high-resolution sensor and high throughput capture camera to secure the detection and rejection of the off-centered tablets during the press coating process.

Interestingly, the camera installed on Skyepharma’s press coater is capable for

• (i) the core’s colour and presence check (wrong core’s colour or absence triggers the tablet rejection),
• (ii) the integrity of the tablet check (30% missing part induces the tablet rejection),
• (iii) the core centering check (any cores outside centering specifications trigger the tablet rejection).

The precision of the centering check is as high as the tenth of a millimeter!

Importantly, like for the multilayer press equipment used for the geomatrix complex tablets manufacturing, the very specific and technical press coater equipment for the geoclock tab-in-tab manufacturing is operated by skyepharma’s highly experienced and skilled teams including both production team and maintenance team who work very closely on the flour to ensure perfect machine running and top-quality products performance every day.

Regular training sessions with both teams are conducted over the years to maintain the highest technical know-how on the press and the best manufacturing versatility.

Skyepharma: expert in complex tablet compression and flexible

One of Skyepharma’s great strengths is its agility and flexibility. Skyepharma expert teams are able to switch from lab scale to pilot scale and to semi-industrial and industrial size equipment according to the client and the projects needs. Indeed, Skyepharma has in particular a Styl’One compression simulator. This equipment is able to mimic with a degree of similarity greater than 95%, the profiles of each of our compression presses, including our Hata multilayer presses or our Kilian press coater.

Supported by its supplier Medelpharm, development issues and troubleshooting are therefore an everyday affair at Skyepharma.

In addition, Skyepharma development teams are closely linked to the industrial manufacturing teams, some of them being former industrial producers for a number of years, allowing for a tremendous level of cohesion, exchange, and flexibility between the teams.

Frédéric CHECOT

Operations Director