Formulation Of Ketoprofen Research Articles

The benefit-risk balance of topical formulations of ketoprofen remains positive,

The benefit-risk balance of topical formulations of ketoprofen remains positive,

The European Medicines Agency's CHMP is conducting a safety review of topical formulations of ketoprofen

The European Medicines Agency's CHMP is conducting a safety review of topical formulations of ketoprofen

Ketoprofen Produces Modality-Specific Inhibition of Pain Behaviors in Rats After Plantar Incision

Postoperative pain remains a significant problem despite optimal treatment with current drugs. Nonsteroidal antiinflammatory drugs reduce inflammation and provide analgesia but are associated with adverse side effects. We tested low doses (0.5-5 mg/kg) of parenteral ketoprofen against pain-related behaviors after plantar incision in rats. To further evaluate the potential sites of action of ketoprofen in our model, a novel, sustained-release microparticle formulation of ketoprofen was placed into the wound, and tested for its effects on pain behaviors. Intrathecal ketoprofen (150 microg) was also studied. Plasma samples were assayed for drug concentrations. We found that low doses of parenterally administered ketoprofen produced a modality-specific effect on pain behaviors; guarding after incision was decreased, whereas no inhibition of exaggerated responses to heat or mechanical stimuli was evident. Very low doses, 0.5 mg/kg, could produce inhibition of guarding. The locally applied sustained-release ketoprofen-eluting microparticles and intrathecally administered ketoprofen also produced a modality-specific effect on pain behaviors after incision, inhibiting only guarding. Plasma levels of ketoprofen after parenteral or local administration were in the range of therapeutic blood levels in postoperative patients. This study demonstrates that ketoprofen is an effective analgesic for nonevoked guarding in rats after plantar incision. There was no effect on mechanical or heat responses, which highlights the importance of multiple-modality testing of pain behaviors for drug evaluation. We found efficacy at doses used clinically in postoperative patients.

Criterion for excipients screening in the development of nanoemulsion formulation of three anti-inflammatory drugs

The present study was undertaken for screening of different excipients in the development of nanoemulsion formulations of three anti-inflammatory drugs namely ketoprofen, celecoxib (CXB) and meloxicam. Based on solubility profiles of each drug in oil, Triacetin (ketoprofen and CXB) and Labrafil (meloxicam) were selected as the oil phase. Based on maximum solubilization potential of oil in different surfactants, Cremophor-EL (ketoprofen and CXB) and Tween-80 (meloxicam) were selected as surfactants. Based on maximum nanoemulsion region in the pseudoternary phase diagrams, Transcutol-HP was selected as cosurfactant for all three drugs. 1:1 (ketoprofen and CXB) and 2:1 (meloxicam) mass ratio of surfactant to cosurfactant was selected for selection of different nanoemulsions on the basis of maximum nanoemulsion region in the phase diagrams. All selected nanoemulsion formulations were found thermodynamically stable. Results of these studies showed that all excipients were properly optimized for the development of nanoemulsion formulation of ketoprofen, CXB and meloxicam.

Functional characterisation of novel analgesic product based on self-regulating drug carriers

We compared a new formulation of ketoprofen (Diractin ®) based on ultradeformable vesicle (Transfersome ®) carriers with conventional topical gels with the drug (Gabrilen ®; Togal ® Mobil Gel; Fastum ®). Depending on water concentration, between a few percent and >95% of ketoprofen in Diractin ® is associated with the vesicles. The low free drug concentration on open skin (1–3%) minimises ketoprofen diffusion from Diractin ® through the organ, keeping effective permeability coefficient for the product (even after increase to ∼3.5 × 10 −3 cm h −1 at 24 h) below that of conventional gels (∼0.3–2.1 × 10 −1 cm h −1). The carrier's stress-responsiveness enables constriction crossing without vesicle breakdown. The carrier stiffening upon dilution, e.g. in tissues below the skin's diffusive barrier, helps avoiding the drug uptake in cutaneous blood capillaries. Diractin ® therefore can deposit ketoprofen in deep subcutaneous tissues, which the drug from conventional gels reaches mainly via systemic circulation. In vitro efficacy of daily drug delivery through skin is ≤1.6% for conventional topical NSAID gels and merely ∼0.05% for Diractin ®. In contrast, in vivo ketoprofen transport by ultradeformable carriers through non-occluded skin into living pigs’ subcutaneous muscles is 5–14× better than for conventional gels. Locally targeted drug transport by the self-regulating, ultradeformable vesicles is thus clearly non-diffusive and quite efficient.

Evaluation of ketoprofen formulations via penetration rate and irritation in vivo study

The purpose of the present study was to design an optimal ketoprofen gel with appropriate penetration rate, shortened lag time and acceptable skin irritation. The combination of different mechanism enhancers including nonivamide, menthol and ethanol were used as multi-enhancers for producing a synergistic enhancement effect and reducing the skin irritation via diminishing the used amount of enhancers. The central composite design was applied to prepare a systemic formulation. The penetration rate (PR), lag time (LT) and skin irritation score (TIS) of a commercial product (Formax plus ® gel containing 3% ketoprofen) were determined by in vivo study and used as a criterion for designed formulations. The PR, LT and TIS of commercial product were 462.2 ± 162.5 μg/h, 0.6 ± 0.1 h and 12.7 ± 0.6, respectively. Among these designed experimental formulations, four formulations including F07 (code: −1/+1/−1), F11 (code: +1/+1/−1), F13 (code: 0/0/−1.732) and F14 (code: 0/+1.732/0), their PR was not smaller and LT and TIS were not greater than that of commercial product, indicating that these experimental ketoprofen gels could be used in the clinical situation.

Pilot Study of Relative Bioavailability of Two Oral Formulations of Ketoprofen 25 mg in Healthy Subjects. A Fast-Dissolving Lyophilized Tablet as Compared to Immediate Release Tablet

ABSTRACTThe pharmacokinetics of ketoprofen from a fast-dissolving lyophilized tablet (LT), which need not be swallowed, as compared to an immediate release (IR) tablet as reference after single oral dose (25 mg) administration was determined in six healthy subjects aged between 25–40 years using a randomized crossover design. In this study, the rate and extent of absorption of ketoprofen were found to be very different after administration of the LT and the IR tablet. The rate of absorption of ketoprofen from LT was significantly faster than that of IR tablet and had significantly higher Cmax (by about 50%) and earlier tmax (by 15 min), whereas the extent of absorption expressed by AUC was about 68% higher as compared to the IR tablet. The relative bioavailability (frel) of the LT compared with the IR tablet was 168%. The difference between the two formulations for half-life and MRT were statistically significant (p < 0.05). The tolerance of the two tested formulations was excellent. Ketoprofen LT remained physically and chemically stable for 12 months at 25°C and 60% relative humidity.

Rapid online-SPE-MS/MS method for ketoprofen determination in dermal interstitial fluid samples from rats obtained by microdialysis or open-flow microperfusion

Pharmacokinetic studies of topical ketoprofen formulations using continuous sampling techniques such as microdialysis (MD) or open-flow microperfusion (OFM) require sensitive assays due to small sample volumes. A simple and easy online-SPE-MS/MS method for ketoprofen analysis was developed for both MD and OFM samples obtained from rat dermal tissue. The quantification range is 25–5000 ng/ml with a limit of detection of 3 ng/ml using only 10 μl sample volume. The method is characterized by a simple setup using a short polymeric SPE column (OASIS HLB) for desalting with 1.5 min run times in combination with a sensitive MS detection in negative ESI MRM mode. An easy sample workup procedure was used which enables high throughput analysis of a large number of samples for pharmacokinetic studies. In addition, a commercial available (fenoprofen) as well as an isotopically labelled (deuterated ketoprofen) standard were investigated as potential internal standards. The method was validated according to FDA guidelines for bioanalytical validation in terms of accuracy, intra-batch and inter-batch precision, linearity, matrix effect, recovery and stability for both internal standards. Accuracies were 98–113% (fenoprofen) and 95–108% (deuterated ketoprofen), intra-batch precision was 2–3% R.S.D. (fenoprofen) and 2–6% R.S.D. (deuterated ketoprofen), and inter-batch precision was 2–6% R.S.D. (fenoprofen) and 3–6% R.S.D. (deuterated ketoprofen) over the entire quantification range. The presented method was applied to dermal interstitial fluid samples obtained in a topical administration study of ketoprofen in rats.

Enantiospecific pharmacokinetic studies on ketoprofen in tablet formulation using indirect chiral HPLC analysis

The present study was undertaken to evaluate the possibility of chiral discrimination in the release of enantiomers of ketoprofen (KT) in tablet form and, in turn, the bioavailability of the individual enantiomers, using the rabbit as a model. The enantiomeric concentration of KT in plasma was determined using a customized chiral HPLC analysis. First the plasma concentration-time profile was established for pure (±) KT in order to assess the extent of chiral discrimination. Subsequently the tablet formulation (Rhofenid-100mg) was administered, at a dose equivalent to 10 mg/kg, to assess the enantiospecific bioavailability of KT enantiomers in the rabbit following the same protocol as followed for the pure KT. In vivo studies revealed that the bioavailability of S-KT is higher than that of the R-enantiomer, after oral dosing with both KT-tablet and KT-pure. But the degree of chiral discrimination is more pronounced and more statistically significant in the case KT formulation as reflected by the enantioselective pharmacokinetic data. The observations presented in this article further emphasize the significance of differentiating between enantiomers of chiral drugs when assessing bioavailability and correlating efficiency with drug concentration. The study opens up a new avenue to the design of stereoselective dosage forms.

Effect of preparation technique on the properties of liposomes encapsulating ketoprofen–cyclodextrin complexes aimed for transdermal delivery

The combined approach of cyclodextrin complexation and entrapment in liposomes was investigated in order to develop an effective topical formulation of ketoprofen. Equimolar complex of drug and hydroxypropyl-β-cyclodextrin (HPβCyd) was added at different concentrations to the aqueous phase of liposomes consisting of phosphatidylcholine and cholesterol (60%/40%, w/w). Liposomes were prepared with different techniques, such as thin layer evaporation, freezing and thawing, extrusion through microporous membrane, and reverse phase evaporation method, obtaining, respectively, multi-lamellar vesicles (MLV), frozen and thawed MLV (FATMLV), small uni-lamellar vesicles (SUV) and large uni-lamellar vesicles (LUV). Size and morphology of the different types of liposomes were investigated by light scattering analysis, transmission electron microscopy, and confocal laser scanning microscopy, whereas drug entrapment efficiency was determined by dialysis experiments. Cyclodextrin complexation improved drug solubilization and allowed a strong improvement of its entrapment into the aqueous liposomal phase. Liposome preparation method and operating conditions clearly affected both liposome size and drug loading capacity. Encapsulation efficiency increased with increasing the complex concentration up to 10 mM, and was in the order MLV > LUV > SUV. An opposite behaviour was observed for FATMLV, probably due to the freezing phase required by such a preparation method, which reduced the complex solubility. Moreover, it was not possible to use higher complex concentrations, due to the destabilizing effect of cyclodextrins toward the liposomal membrane. Permeability studies of drug–HPβCyd complexes, directly in solution or incorporated in liposomes, performed across artificial membranes simulating the skin behaviour, highlighted, as expected, a prolonged release effect of liposomal formulations. Furthermore, the drug permeation rate depended on the vesicle characteristics and varied in the order: SUV > MLV = FATMLV > LUV. Therefore, the most suitable liposome preparation method can be suitably selected on the basis of drug encapsulation efficiency and/or desired drug release rate.

Dexketoprofen trometamol in post-operative pain management

Abstract Dexketoprofen trometamol is the dextrorotatory enantiomer of ketoprofen formulated as the tromethamine salt. Producing a single isomer formulation of ketoprofen simplifies the pharmacokinetics of the drug and allows a 50% reduction in dosage. This may reduce adverse effects by reducing metabolic and renal load. Formulation as the tromethamine salt results in faster absorption from the gut and therefore quicker onset of analgesia. This paper reviews studies of the use of dexketoprofen in acute postoperative pain, and concludes that it produces rapid and reliable onset of analgesia.

In vivo evaluation of matrix pellets containing nanocrystalline ketoprofen

The aim of this study was to evaluate the in-vivo behaviour of matrix pellets formulated with nanocrystalline ketoprofen after oral administration to dogs. No significant differences in AUC-values were seen between pellet formulations containing nanocrystalline or microcrystalline ketoprofen and a commercial ketoprofen formulation (reference: Rofenid® 200 Long Acting). C max of the formulations containing nano- or microcrystalline ketoprofen was significantly higher compared to reference, whereas t max was significantly lower. The in-vivo burst release observed for the spray dried nanocrystalline ketoprofen matrix pellets was reduced following compression of the pellets in combination with placebo wax/starch pellets. These matrix tablets sustained the ketoprofen plasma concentrations during 5.6 and 5.4 h for formulations containing nano- and microcrystalline ketoprofen, respectively.

Release of ketoprofen enantiomers from HPMC K100M matrices—diffusion studies

Sustained release formulations of ketoprofen elaborated with HPMC K100M were studied to test the hypothesis that chiral excipients can stereoselectively affect the release of the racemic drug. The differences observed in the percentage released between enantiomers show the existence of a chiral interaction between ketoprofen and HPMC K100M. HPMC interacts preferably with the S-enantiomer, although the enantioselectivity observed was not relevant from biopharmaceutical and clinical points of view. Diffusion studies were carried out in membrane diffusion cells to simplify the excipient–drug system and hence to analyze only the influence of diffusion process on the stereoselectivity. The results obtained show that the absence of the erosion process strengthens the enantiomeric differences observed in the drug release from tablets. Another objective of this work was to study the influence of formulation pH on the ‘in vitro’ release profile of ketoprofen. The amount and the release mechanism of ketoprofen from formulations elaborated are conditioned mainly by the pH of the matrix.

Influence of a polymeric formulation of ketoprofen on its diffusion into cerebrospinal fluid in rats

Poly( d,l)lactide nanocapsules (NCs) have been proposed as an alternative carrier for many drugs. We investigated the influence of this formulation on the pharmacokinetics of ketoprofen in the plasma and cerebrospinal fluid (CSF). Male Wistar rats were given intraperitoneal dose of ketoprofen (5 mg/kg) in a suspension of NCs or in a carboxymethylcellulose (CMC) solution (reference preparation). Blood and CSF samples were collected at different times up to 24 h after dosing. The unbound fraction of ketoprofen in plasma ( f u) was determined using ultrafiltration. The total ( C T) and free ( C F) concentrations of ketoprofen in plasma and the simultaneous CSF concentrations ( C CSF) were measured by a HPLC method and the areas under the curve (AUC T, AUC F, AUC CSF) were calculated. AUC T of ketoprofen-loaded NCs in plasma was similar to that of the reference solution, while AUC F of the former (5.41 mg/l×h) was higher than that produced by the latter (4.03 mg/l×h). Accordingly, the unbound fraction ( f u) was higher after administration of NCs than that of the solution (2.5 and 1.8%, respectively). Finally, AUC CSF were identical for both formulations. These findings suggest that the binding of ketoprofen to plasma proteins is not the major factor that governs its blood-to-CSF exchanges.

Evaluation of percutaneous absorption and skin irritation of ketoprofen through rat skin: in vitro and in vivo study

The influences of different mechanisms of penetration enhancers (such as menthol, azone, ethanol and nonivarnide) regarding the percutaneous absorption and skin irritation of ketoprofen formulations through rat skin were investigated by in vitro and in vivo study. The skin irritation degree at the end of the experiment (10 h) was deterinined by pathologic biopsy and colorimetry methods. In vitro, the menthol showed the most potent enhancing effect. Furthermore, the enhancement effect of a combination of menthol and nonivamide was higher than that of their individual use alone. In vivo the formulation containing 0.05% nonivantide, 5% menthol and 20% ethanol showed a higher penetration rate and an acceptable degree of skin irritation compared to a commercial product (Formax plus® gel containing 3% ketoprofen), indicating that it could be used in the clinical situation.

An oral controlled release matrix pellet formulation containing nanocrystalline ketoprofen

A controlled release pellet formulation using a NanoCrystal ® colloidal dispersion of ketoprofen was developed. In order to be able to process the aqueous NanoCrystal ® colloidal dispersion into a hydrophobic solid dosage form a spray drying procedure was used. The in vitro dissolution profiles of wax based pellets loaded with nanocrystalline ketoprofen are compared with the profiles of wax based pellets loaded with microcrystalline ketoprofen and of a commercial sustained release ketoprofen formulation. Pellets were produced using a melt pelletisation technique. All pellet formulations were composed of a mixture of microcrystalline wax and starch derivatives. The starch derivatives used were waxy maltodextrin and drum dried corn starch. Varying the concentration of drum dried corn starch increased the release rate of ketoprofen but the ketoprofen recovery remained problematic. To increase the dissolution yield surfactants were utilised. The surfactants were either added during the production process of the NanoCrystal ® colloidal dispersion (sodium laurylsulphate) or during the pellet manufacturing process (Cremophor ® RH 40). Both methods resulted in a sustained but complete release of nanocrystalline ketoprofen from the matrix pellet formulations.

Topical Oleo-Hydrogel Preparation of Ketoprofen with Enhanced Skin Permeability

In an attempt to improve the skin penetration of ketoprofen, various transdermal formulations were prepared, and their in vitro skin permeability and in vivo percutaneous absorption were evaluated. In vitro permeation studies were performed using a modified Franz cell diffusion system in which permeation parameters such as cumulative amount at 8 hr Q8hr, steady-state flux Jss, or lag time tL were determined. In the in vivo percutaneous absorption study using the hairless mouse, maximum concentration Cmax and area under the curve at 24 hr AUC24h were measured. The optimal transdermal formulation (oleo-hydrogel formulation) of ketoprofen showed a Q8hr value of 227.20 μg/cm2, a Jss value of 29.61 μg/cm2/hr, and a tL value of 0.46 hr. The Q8hr and Jss values were about 10-fold (p <. 01) higher than those (Q8hr = 19.61 μg/cm2; Jss = 2.66 μg/cm2/hr) from the K-gel and about 3.5-fold (p <. 01) than those (Q8hr = 60.00 μg/cm2; Jss = 7.99 μg/cm2/hr) of the K-plaster. In the in vivo percutaneous absorption, the Cmax (6.82 μg/ml) and AUC24h (55.74 μg·hr/ml) values of the optimal formulation were significantly (p <. 01) higher than those of K-gel and K-plaster. The relative bioavailability of the oleo-hydrogel following transdermal administration in reference to oral administration was about 37%, and the Cmax value (4.73 μg/cm2) in the hypodermis following topical administration was much higher than those from the conventional products (Cmax of K-gel and K-plaster were 0.92 ± 0.19 μg/cm2 and 1.27 ± 0.37 μg/cm2, respectively). These data demonstrate that the oleo-hydrogel formulation of ketoprofen was more beneficial than conventional products (K-gel and K-plaster) in enhancing transdermal permeation and skin absorption of ketoprofen. Furthermore, there was a good correlation between in vitro permeation parameters and in vivo percutaneous absorption parameters.

The effect of ketoprofen creams on periodontal disease in rhesus monkeys.

Ketoprofen creams were evaluated for the treatment of periodontal disease in a placebo-controlled, double-blind study in the rhesus monkeys, Macaca mulatta. Two formulations containing ketoprofen (1%), with or without vitamin E, were evaluated against appropriate controls (8 monkeys per group). Two weeks prior to treatment, the animals received prophylaxis on only the left side of the mouth (spontaneous model). Selected teeth on the right side of the mouth were ligated (ligature model). The creams were administered to the gingiva once daily at a standard dose of 1.8 ml per monkey for 6 months. Clinical assessments were made 2 wk before initiation, at baseline and 1, 2, 3 and 6 months post-treatment. The clinical parameters included plaque formation, gingival redness, edema, bleeding on probing and Ramfjord Attachment Level measurements (RAL). Radiographs were taken at 2 wk before initiation, baseline and at 3 and 6 months post-treatment. Digital, subtraction radiography was used to measure vertical linear bone loss along the interproximal root surfaces of the left and right mandibular first molars. Gingival crevicular fluid (GCF) was collected for biochemical assays on PGE2, TxB2, LTB4, IL-1 beta and TNF alpha. There were no significant differences among groups with respect to gingival indices. Radiographic data demonstrated significant positive effects on bone activity in both groups treated with ketoprofen formulations with improvement over time in the ligature model (0.01 < or = p < or = 0.04). The placebo group exhibited bone loss of 1.96 +/- 0.48 and 1.40 +/- 0.56 mm per site at 3 and 6 months, respectively. The group treated with ketoprofen cream showed an apparent bone gain of 0.28 +/- 0.41 and 0.78 +/- 0.47 mm per site at 3 and 6 months, respectively. The group treated with ketoprofen cream containing vitamin E showed a mean bone loss of 0.41-0.48 mm per site at 3 months with improvement to an apparent bone gain of 0.31 +/- 0.44 mm per site at 6 months. The biochemical data demonstrated early and significant suppression of GCF-LTB4 by both ketoprofen formulations at 1 month, which preceded the significant suppression of GCF-PGE2 at 2 and 3 months in the ligature model (p < 0.003) and at 2 to 6 months in the spontaneous model (p < 0.02). We conclude that ketoprofen at 1% level in suitable topical vehicles can effectively inhibit GCF-LTB4 and GCF-PGE2 and positively alter alveolar bone activity in the ligature-induced model of periodontitis in the monkey.

Development of Controlled Release Formulations of Ketoprofen for Oral Use

AbstractMicroencapsulated forms of ketoprofen were formulated using polymers and polymer combinations and their in-vitro release characteristics were evaluated against pure ketoprofen using Vanderkamp 600 dissolution test apparatus. Suspensions of cellulose acetate phthalate were prepared and various quantities of drug, glycerin, tween 80, span 80, methocel and avicel were added and the resulting solution was passed through a peristaltic pump into a hardening solution. Beads were formed, dried and the release of the drug was studied at various time intervals in a dissolution medium of simulated intestinal pH. The dissolution studies of the ketoprofen demonstrated differences in drug release properties depending on composition and method of preparation. A formulation of Methocel beads with equal proportions of the two surfactants released its drug content over a period of 12 hours in a zero-order fashion. Rapid drug dissolution was seen when the formulations contained Tween 80 as a surfactant. Varying the ...

Channelling of controlled release formulation of ketoprofen (Oscorel) in patients with history of gastrointestinal problems.

The aim was to determine if a new controlled release formulation (Oscorel) of the non-steroidal anti-inflammatory drug (NSAID) ketoprofen has been preferentially prescribed in patients with prior history of gastro-intestinal disturbances. The study was a pharmacy records based comparison of the rates of prior prescribing of drugs indicated for peptic ulcer treatment in first recipients of Oscorel in 1989 versus recipients of other NSAID products. A representative panel of Dutch community pharmacies serving approximately 425,000 people was used. Oscorel was launched in January 1989. Data on prescriptions dispensed in 1987-1988 to a total of 837 first users of Oscorel were analysed and compared with the dispensing history of a reference population including 30,787 patients who did not receive a prescription for Oscorel during 1989. Compared to the reference population, first users of Oscorel included a greater proportion of females, of patients 75 years and older, of heavy users of NSAIDs, and of patients switching among different NSAIDs. A total of 24.1% of first users of Oscorel had received peptic ulcer therapy in 1987-1988, versus 15.7% of the reference population. The rate ratio was 1.54, with 95% confidence interval of 1.36-1.74. Adjustment for stratifying variables caused only minor changes in the rate ratio, which remained stable on 1.5. Oscorel appears to have been channelled into use in patients with recognised risk factors for gastrointestinal toxicity. This preferential prescribing probably resulted from expectations and claims that this product has a lower risk of such toxicity.