How to achieve targeted delivery of the poorly soluble active ingredient dipyridamole

Study carried out using Gamlen Tablet Press

Introduction

The poor physicochemical properties of many drugs present challenges when targeting delivery to site-specific regions of the gastrointestinal tract for either a systemic or topical effect.

For poorly soluble basic drugs administered by the oral route, often delivery in a salt form is favoured since within the low pH environment of the stomach the drug is maintained in an ionised state, which often leads to significant improvements in aqueous solubility. However, post gastric emptying, upon transit into the proximal small intestine there is a rapid pH shift to more basic conditions, which can lead to uncontrolled precipitation of the neutral species of the drug. As the drug needs to in solution at the site of absorption, this precipitation can lead to varied or low bioavailabilities when dosed orally.

In order to overcome this challenge, drugs are often formulated in enteric dosage forms, however, typically they do not generally release drug into the small intestine until 1-2 hours post gastric emptying. As small intestinal transit is known to be relatively constant at 3-4 hours, this can greatly reduce the proportion of the dose available for systemic absorption, especially if drug absorption occurs in the proximal small intestine region1. Therefore, for basic drugs a formulation is often required whereby the drug is released directly at the site of absorption in a physical or chemical state that affords sufficient solubility/dissolution kinetics in the biological fluid media.

Aims

This aim of this work was to investigate the use of a single unit nonenteric coated dosage form to achieve site-specific delivery of the basic drug dipyridamole to the proximal small intestine region of the gastrointestinal tract. A novel pHresponsive enteric microparticle formulation (ProRelease™) was evaluated which enables encapsulation of the drug in a molecularly dispersed amorphous state, allowing for targeted drug delivery as well as rapid dissolution/enhanced kinetic solubility at the site of absorption.

Results and discussion

A simple emulsification/solvent evaporation method was successfully optimised using only non-toxic solvents in the manufacturing process for the production of dipyridamole loaded Eudragit L microparticles.

SEM revealed that the formed particles exhibited excellent morphology, being spherical, non-porous and non-aggregated and with a narrow size distribution (Figure 1). Drug encapsulation efficiency was approximately 95 % and pXRD measurements confirmed the drug was encapsulated in the amorphous state, with little/no crystalline content evident (data not shown).

formulation-aims-1Figure 1 SEM of dipyradamole loaded microparticles

Microparticles were subsequently compressed into microtablets using suitable GRAS excipients on the GTP1. The selection of excipients was evaluated in order to produce a tablet that was non friable but enabled rapid disintegration and microparticle release when dispersed in an aqueous environment. Particles, tablets and the dissolution profile of the product are shown below:

formulation-aims-2Figure 2 Dipyridamole microtablet

formulation-results_old

Figure 3 In- vitro drug release of dipyradamole under varying pH conditions simulating A) stomach B) proximal small intestine

After storage at pH 1.2 for 2 hours, no drug dissolution was observed and the particles remained freely suspended, with little / no particle agglomeration evident. The lack of drug release at this low pH showed that the particles conformed to the specifications of the United States Pharmacopeia 24 for enteric coated products, i.e.  that an enteric dosage form should not release more than 10% of its drug load in 2 h exposure to 0.1M HCl pH 1.2.  Upon increasing the pH to 6.8 (i.e. above the pH threshold of the polymer and simulating proximal small intestinal conditions), rapid particle dissolution was observed and complete drug release was detected within 10 minutes.

 

Gamlen-Tablet-Press-laborat

 

 

 

 

 

 

 

 

 

Why use a Gamlen Tablet Press?

It can save you time, money and materials. People need help to study tablets under properly controlled conditions in a laboratory.

Michael Gamlen invented the Gamlen Tablet Press (GTP) to help you understand the relationship between the properties of your drug, formulation, and manufacturing process. When you do this you can develop better products more quickly, and improve productivity of your tablet manufacturing operations.

The GTP is the first machine designed to make tablets on a small scale at a user-specified compaction force. This force determines both the physical strength and the dissolution behaviour of the tablet. These are the key properties which ensure the tablet reaches the patient and delivers the drug.

The machine works by monitoring the force in real time using a PLC.  The punch force and punch position are displayed in real time on a computer which is also used to input the compaction conditions. Using the GTP we make tablets of extraordinary reproducibility and consistency, within 1-2% force, and with no wastage. Batch yields are >99%.

For the measurement of tablet breaking load, the press records both force and displacement during both compression and fracture, and also provides the ejection force profile associated with tablet ejection

In the scale-up of tablet production, the press can be used to determine the relationship between tablets developed at the bench-top scale using a few grams of material (often at the early development stage) and the final tablet manufactured on a rotary tablet press. The latter uses hundreds of kilograms of material, making process development difficult because of practical difficulties in experimentation; smaller and different shaped tablets can, however, be scaled to the final desired tablet design if TFS is used as the basis for comparison.

If you want better tablet products and processes you need the Gamlen Tablet Press.

Conclusions

A novel single unit micro-tablet formulation was successfully developed for the simulated targeted delivery of the basic drug dipyridamole to the proximal small intestine region of the gastro-intestinal tract. The application of the technology may be particularly beneficial for the oral delivery of poorly soluble basic drugs, preventing uncontrolled drug precipitation post gastric emptying and providing rapid drug release and high local drug concentrations at the appropriate site of absorption.

Have a question? Like a quotation?
Like to see a Gamlen Tablet Press demo 
or have batch tablet samples made?

Then email michael.gamlen@gamlentableting.com
or call us now on +44 115 912 4271

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