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Compatibility between Diclofenac Sodium and a Novel Bacillus-derived Hyaluronic Acid and Release of Diclofenac Sodium from Hyaluronic Acid-containing Preparations towards the Treatment of Osteoarthritis
C. Eenschooten1, O. Møller Dall1, B. Kaufmann2, F. Longin1, R. Gurny2, K. Schwach-Abdellaoui11Novozymes Biopharma DK A/S, Bagsvaerd, DK-2880, Denmark; 2University of Geneva (EPGL), Geneva-4, CH-1211, Switzerland
Osteoarthritis is the most common degenerative joint disease which affects
Bacillus-derived hyaluronic acid features excellent compatibility with Bacillus-derived hyaluronic acid significantly prolongs the release of
more than 50% of people over the age of 65 worldwide. It is mainly
diclofenac sodium diclofenac sodium from a commercial formulation
characterized by symptoms such as cartilage loss and synovial fluid
Bacillus-derived HA and diclofenac sodium were formulated in a model
Bacillus-derived HA was added to the commercial injectable formulation
degradation which causes bone surfaces to come in contact and results in
injectable formulation and their compatibility was investigated overtime and as
Voltaren® (Novartis International AG) at different concentrations and the
release of diclofenac sodium from the resulting preparations was investigated
Possible treatment strategies consist in injecting nonsteroidal anti-
Figure 1 shows that Bacillus-derived HA did not undergo depolymerization in
inflammatory drugs (NSAIDs) or hyaluronic acid (HA) viscosupplement
the presence of diclofenac in the model formulation. It was stable over the
Figure 3 shows that while diclofenac release from the commercial product was
formulations intra-articularly. However no combination products allying the
time period tested at all temperatures.
already completed after 11 min, the latter could be extended up to 10 hrs by
benefits of both ingredients exist to date.
the addition of HA into the commercial formulation (Table 1, a)). This can be
attributed to the higher viscosity of HA-containing formulations which can
entrap active molecules and retard their outward movement.
to evaluate the compatibility between a novel Bacillus-derived HA and
the NSAID diclofenac sodium in a model injectable formulation
For comparison purposes, the release of diclofenac (suspended or dissolved)
was also studied from phosphate-buffered HA solutions at the same
to investigate the ability of HA to prolong the release of diclofenac from
concentrations (Table 1, b). Release time values were in the same range as
those observed with HA-supplemented Voltaren® formulations and overall were
independent of the initial state of diclofenac in the preparation. METHODOLOGY Voltaren® Voltaren® + 1% HA Model injectable formulation Voltaren® + 2% HA
The model injectable formulation (pH 7.5) was prepared aseptically by
Voltaren® + 3% HA
dissolving diclofenac sodium (250 mg), mannitol (460 mg), propyleneglycol
(1,000 mg), acetylcysteine (10 mg), benzyl alcohol (400 mg), and Bacillus-
derived HA (10 mg) in water for injection (10.0 mL). Compatibility study
The compatibility between Bacillus-derived HA and diclofenac sodium in the
Time (days)
model injectable formulation was evaluated by following the stability of both
Fig. 1. Percentage residual HA molecular weight as a function of time and storage
ingredients as a function of time and storage temperature. HA and diclofenac
temperature.
stability was assessed by residual molecular weight and concentration
Figure 2 shows that diclofenac concentration was the same after 8 weeks of
measurements, respectively. The various preparations were stored at 5, 25 and
storage. Diclofenac was not degraded in the presence of Bacillus-HA in the
model formulation independently of the temperature tested.
The molecular weight of HA was determined by gel permeation
chromatography combined with triple-angle light scattering and refractive
index detection. Columns: Waters Ultrahydrogel 2000, 1000, 250 and 120
Release time (hrs)
thermostatized at 25 C. Mobile phase: 50 mM NaH2PO4, 150 mM NaCl, 0.05%
Fig. 3. Percentage dissolved diclofenac from Voltaren® formulations supplemented with HA at different concentrations.
Diclofenac residual concentration was quantified by HPLC with UV detection at
280 nm. Column: Phenomenex Luna PFP 150x4.6 mm, 3 μm, thermostatized
Table 1. Diclofenac release time (98%) from a) Voltaren® formulations supplemented with HA
at 25 C. Mobile phase: water + 0.1% (w/v) TFA / acetonitrile + 0.1% (w/v)
at different concentrations, b) HA hydrogel solutions at different concentrations.
TFA in the proportion 30:70. Flow rate: 1 mL/min. Injection volume: 10 μL. Diclofenac release time (min) HA concentration (% w/w) b) diclofenac suspended b) dicofenac dissolved Release study
HA (898,000 Da) was added to the commercial injectable formulation
® (Novartis International AG) at a concentration ranging from 1 to 3%
As control experiments, diclofenac sodium was either dissolved or suspended
into phosphate-buffered HA solutions with a concentration ranging from 1 to
CONCLUSION
3% (w/w). The solutions were obtained by mixing phosphate-buffered HA
solutions with a solution of diclofenac in polyethylene glycol.
The data presented here demonstrate that under the conditions tested
All formulations contained a total of 20 mg of diclofenac. Storage temperature
Bacillus-derived hyaluronic acid and diclofenac sodium are highly
The release of diclofenac from the resulting HA-containing preparations was
Fig. 2. Percentage residual diclofenac concentration at week 8 as a function of storage
assessed by dissolution with UV detection at 276 nm using a closed loop
temperature.
The addition of Bacillus-derived HA to a commercial injectable
system configuration. Instrument: SOTAX CE7smart. Method: USP 4
formulation significantly prolongs the release of diclofenac
dissolution method. Cell type and volume: 22.4 mm, 100 mL. Buffer: PBS (pH
The initial state of diclofenac in the preparation has little influence on
7.0). Temperature: 37 C. Flow rate: 4 mL/min. Stirring speed: high.
These findings suggest combining the individual benefits of HA and diclofenac
sodium in future intra-articular formulations intended to the treatment of
osteoarthritis. For further information, please visit us at Booth #301
Address: Novozymes Biopharma DK A/S, Krogshoejvej 36, DK-2880 Bagsvaerd, Denmark
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INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICALREQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMANUSE DRAFT CONSENSUS GUIDELINE THE COMMON TECHNICAL DOCUMENT FOR THE REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE EFFICACY At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the appropriate ICH Expert Working Group, is transmitted by the ICH Steer
Compatibility between Diclofenac Sodium and a Novel Bacillus-derived Hyaluronic Acid