SUSTAINED RELEASE MULTI-PARTICULATES FORMULATION OF STEREO-SELECTIVE MOLECULE OF KETOPROFEN BY FLUID BED PROCESSOR

SUSTAINED RELEASE MULTI-PARTICULATES FORMULATION OF STEREO-SELECTIVE MOLECULE OF KETOPROFEN BY FLUID BED PROCESSOR

Bhupendra G. Prajapati ^* and Alpesh Patel

Department of Pharmaceutics, Shree S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Ganpat Vidyanagar, Kherva, Mehsana - 384012, Gujarat, India.

ABSTRACT: The aim is to prepare sustained release multi-particulates dosage form of Dexketoprofen trometamol, which is the active isomer of ketoprofen. Utilization of active moiety with minimum drug dose and administration frequency sustained-release multi-particulates dosage form is explored. Sustained release pellets of the dexketoprofen trometamol were developed by the fluidized bed technology, in which drugs along with a binder and anti-adherent agents, were loaded onto microcrystalline cellulose inert beads. These drug-loaded pellets were again coated with Kollicoat SR 30D as sustained-release coating polymer, triethyl citrate as plasticizer and talc as an anti-adherent. The formulation was further statistically optimized for agglomerates formation, process efficiency, and drug release profile using central composite design (CCD). Results show that 16.9 to 18.5% w/w sustained release coating with 9.0-14.6% w/w talc and 8.1 to 16.5% w/w triethyl citrate concentration gives desired drug product quality attributes. Sustained-release multi-particulates were successfully developed for dexketoprofen trometamol, which maybe explored to manufacture various dosage forms like capsules, compressed tablets, pellets in sachet etc. for ease of patient compliance.

Dexketoprofen Trometamol, Pellets, Fluid Bed Technology, Central composite design

INTRODUCTION: Chirality phenomenon has play a major role in the synthesis and development of new drug therapy to achieve better therapeutics index ¹. A molecule is referred to as chiral if it is not superimposable to its mirror image. The best example of chirality is our hand ². Majority molecules of importance to living systems are chiral e.g., amino acids, sugars, proteins, and nucleic acids ³. Major advantages of chiral switching include: (1) an improved therapeutic index through increased potency and selectivity and decreased side-effects; (2) a faster onset of action; (3) a reduced propensity for drug-drug interactions, and (4) exposure of the patient to a lower dosage ⁴.

Dexketoprofen trometamol (DT) is a water-soluble salt of the dextrorotatory enantiomer of the NSAID ketoprofen ⁵. Racemic Ketoprofen has been used since 1973 as an anti-inflammatory, analgesic and antipyretic active drug substance and is one of the most potent in-vitro inhibitors of prostaglandin synthesis ^{6, 7}. Dexketoprofen trometamol adminis-tration was found to be highly effective in treatment of moderate to severe pain when used as an analgesic in osteoarthritis, dysmenorrhea, gynecologic, orthopedic, and dental surgery ⁸. This effect is because of the S (+)-enantiomer of dexketoprofen while R (-) - enantiomer is devoid of such action ⁹. DT is not official in any pharmacopeia ⁶.

DT is well absorbed in the gastrointestinal tract when administered orally owing to its high aqueous solubility. Commercial oral DT tablets are needed to be administered 3-6 times daily due to DT’s shorter elimination half-life (1.2-2.5 h) ¹⁰. Additionally, side effects of oral immediate-release DT tablets include gastrointestinal disturbances such as gastrointestinal discomfort, nausea, diarrhea, and gastrointestinal bleeding like other NSAIDs. A sustained-release oral formulation of DT has the potential of reducing the frequency of administration and side effects and thus improve patient compliance.

These multiple-unit doses are usually formulated in the form of suspensions, capsules, or orally disintegrating tablets, showing a number of advantages over the single-unit dosage system. The subunits of multiple-unit preparations distribute readily over a large surface area in the gastrointestinal tract, and these small particles (<2 mm) behave like liquids leaving the stomach within a short period of time. Their small size also enables them to be well distributed along the gastrointestinal tract that could improve the bioavailability, which potentially could result in a reduction in local drug concentration, risk of toxicity, and side-effects ¹¹.

Widely used techniques to manufacture sustained-release pellets are extrusion-spheronization and bottom spray fluidized bed coating process. Amongst these two techniques, extrusion-spheronization is a shorter process compare to fluidized bed coating but produce the irregular  size of pellets which leads to variation in drug product critical quality attributes (i.e., drug release). Therefore to achieve narrow particle size distribution and batch to batch consistency in terms of finished product quality, a fluid bed coating technique is more preferable.

During this research work, drug loading was done on microcrystalline cellulose (MCC) spheres (Celphere CP 305) using a various drug to binder ratio to provide maximum drug loading process efficiency. Neutral, insoluble substrate without smell or odor, having high mechanical strengths, and narrow particle size distribution make these Celphere CP 203 as a good candidate for drug loading and sustained release coating in wurster coating process. This drug-loaded pellets are then coated with Kollicoat SR 30D as sustained-release coating polymer, triethyl citrate as plasticizer, and micronized talc as an anti-tacking agent to get final pellet size of 400-700 micron. During research work, sustained-release coated pellets were also optimized using statistical design i.e., central composite. Sustained release pellets were evaluated for particle size by sieve analysis, coating process efficiency, and dissolution.

MATERIALS AND METHODS:

Materials: Dexketoprofen trometamol (Emcure Pharmaceuticals Ltd) was used as a model drug. MCC spheres (300-500μm, Celphere CP-305, Asahi KASEI, Japan) were selected as a substrate for coating. Polyvinyl pyrrolidone (Kollidon 30, BASF Germany) was selected as a binder during drug loading process. Triethyl citrate (Merck) was used as plasticizer during sustained release coating process. Micronized talc (Luzenac Pharma M, Imerys) was selected as anti-tacking agent during drug loading and sustained release coating process.

Manufacturing of Drug-Loaded Pellets: Drug loading of dexketoprofen trometamol was performed onto MCC sphere (300-500 μm, Celphere CP-305, Asahi KASEI, Japan) by applying drug layering suspension of dexketoprofen trometamol, which is prepared by dissolving dexketoprofen trometamol into purified water with different binder concentration. Binder concentration was selected in a range of 0-7.5% of drug. Micronized talc (2% of drug) is added to the solution to minimize static charge generation and agglomerates formation during spraying process¹². Drug loading was done in Wurster coater (ACG Pam Glatt, Model: GPCG 1.1). The final drug-loaded pellets have 110.625 mg of dexketoprofen trometamol in 218.370 mg of drug pellets.

TABLE 1: COMPOSITION OF DEXKETOPROFEN TROMETAMOL DRUG LOADED PELLETS

Manufacturing of Sustained Release Coated Pellets: Sustained release coating on drug-loaded pellets were done using liquid dispersion of Kollicoat SR30 D as sustained-release polymer which contains polyvinyl acetate (PVAc, 27%) stabilized with polyvinyl pyrrolidone (PVP, Povidone, 2.7%) and sodium lauryl sulphate (SLS, 0.3%), Triethyl citrate as a hydrophilic plasticizer and micronized talc as an anti-tacking agent. Sustained-release coating was done in a range of 10-28% with solid dispersion content of 20% w/w. Triethyl citrate was used as a plasticizer at 10% w/w concentration of dry polymer solid weight, and Talc was added as an anti-tacking agent at 5% w/w concentration of total solid material. To prepare sustained release coating dispersion (20% w/w), the Part quantity of purified water was added into the dispersion under mild stirring. TEC was added to this dispersion and stirred for 30 min to make homogeneous dispersion. Talc was dispersed into remaining purified water under continuous stirring, and this dispersion was added to previously prepared polymer dispersion. This dispersion was filtered through #60 to remove any lumps in dispersion.

This dispersion was then sprayed onto drug-loaded pellets too get final sustained-release coated micropellets of 400-700 µm. Till the completion of the spraying process, the dispersion was continuously stirred to avoid talc sedimentation.

TABLE 2: COMPOSITION OF DEXKETOPROFEN TROMETAMOL SUSTAINED RELEASE COATED PELLETS

TABLE 3: COATING PROCESS PARAMETERS

Statistical Optimization of the Sustained Release Coating: After getting satisfactory results for drug release from the feasibility trial of sustained-release coated pellet, % sustained release coating, amount of plasticizer and anti-tacking agent in sustained-release coating formulation were optimized using design of experiment tool, i.e., central composite design (CCD Design). During optimization study, solid content in dispersion was kept constant at 20% w/w. As % sustained release coating weight gain, amount of plasticizer, and anti-tacking agent exhibits an important role for controlling drug release from pellets, these factors were selected as independent parameters during formulation optimization study using central composite design using three center points. The dependent responses were selected as the amount of agglomerates and drug release at 1, 4, 7, and 10 h.

TABLE 4: SUMMARY OF CCD DESIGN

Evaluation of Pellets: Drug loaded pellets and sustained-release coated pellets were evaluated for particle size distribution by using an analytical sieving method. Coating process efficiency (% w/w) was calculated for both drug loading and sustained release coating process using the following equation.

% Coating process efficiency = Wt. of Final Coated Pellets – wt. of Starter Pellets × 100 / Amount of Solid sprayed from dispersion

Assay of drug-loaded pellets was carried out to determine the actual drug content inside the drug pellets. Sustained-release coated pellets were evaluated for in-vitro drug release in 500 mL SGF (pH 1.2) followed by SIF (pH7.4) using paddle apparatus (USP Apparatus –II) at 50 RPM. Drug release was compared to marketed product Oruvail 150 mg (Ketoprofen Capsules) by similarity factor (f₂), mean dissolution time (MDT), and mean residence time (MRT). An f2 value between 50- 100 suggests that the two dissolution profiles are similar, and the mean dissolution profiles are assumed to differ by no more than 10% at any time point ^{13, 14}.

Where Rt and Tt are the per cent dissolved at each time point for reference (R) and test (T) products.

RESULTS:

Preliminary Trials of Drug Loaded Pellets: Process efficiency is one of the important critical quality attributes for effective drug loading process and to control the amount of drug-loaded onto pellets (i.e., assay). Wurster coating process involves many dependent and independent variables which affect process efficiency. The preliminary trial drug-loaded pellets were taken to study binder amount level on drug pellets assay, process efficiency, agglomerates, and fines formation, which are summarized in Table 5.

Process feasibility was defined as completion of process without any agglomerates observation, and the intermittent process stops. Ranking for Process feasibility was assigned as 1 (Very poor), 2 (Poor), 3 (Good), 4 (very good).

TABLE 5: RESULTS OF DRUG LOADED PELLETS OF DT

Preliminary Trials of Sustained Release Coating: Preliminary trials of sustained-release coated pellets were evaluated for % process efficiency, assay, particle size distribution, and drug release profile.

TABLE 6: RESULTS OF SUSTAINED RELEASE PELLETS

TABLE 7: DRUG RELEASE PROFILE OF SUSTAINED RELEASE PELLETS

FIG. 1: COMPARATIVE DISSOLUTION PROFILE OF DIFFERENT SUSTAINED RELEASE COATING WEIGHT GAIN BATCHES

TABLE 8: RESULTS OF SUSTAINED RELEASE COATING OPTIMIZATION USING CCD DESIGN

DISCUSSION:

Drug Loading: Binder quantity play crucial role in adhesion of drug onto inert starter core pellets. Low binder concentration in drug layering suspension may results in powder loss during the drug loading process, which reduces assay of drug pellets. Higher binder concentration yields viscous and sticky dispersion, which results in agglomerates generation due to sticking of pellets with each other that necessitates slow spray rate and higher product bed temperature. Binder optimization trial in drug loading showed that there was an increase in process efficiency with an increase in the binder concentration. 5 & 7.5% w/w concentration of Povidone K30 with respect to drug amount gives greater than 90% process efficiency while a higher amount of agglomerates were observed for drug layering trial with 7.5%.

Based on preliminary trials for drug loading, Povidone concentration is selected as 5% of drug substance quantity. This gave good process feasibility and good adhesion of the drug onto the MCC pellets. Talc at 2% of total drug layering solid mass shows better anti-tacking property to remove unnecessary static charges as well as agglomeration generation during spraying process.

Sustained Release Coating: Sustained release coating formulation and process both play vital role in controlling drug release from the pellets. The feasibility trials for sustained release coating were taken by applying different % of weight gain. As the coating weight gain increases from 10 to 28% w/w, the drug release profile significantly decreases. 16% w/w weight gain give comparable drug release to that of the marketed product (Oruvail- Ketoprofen Extended-Release capsules) with f2 value of above 50. Even Mean dissolution time (MDT) and mean residence time (MRT) of pellets is comparable to that of a brand product. This selected 16% w/w coating weight gain was further optimized by varying levels of components to get appropriate robust formulation, which gives satisfactory quality attributes of dosage forms within narrow possible changes.

Sustained Release Coating Formulation Optimization: Sustained release coating formula optimization was done using response surface methodology i.e., CCD design with three center point. Three dependent responses were investigated, which are amount of agglomerates, coating process efficiency, and drug release at 1, 4, 7, and 10 h. Fit summary of various investigated dependent responses were summarized in Table 9.

TABLE 9: FITS SUMMARY OF RESPONSES UNDER STUDIED

TABLE 10: ANOVA RESULT OF DEPENDENT PARAMETERS (Y₁: AGGLOMERATES)

ANOVA results for agglomerate shows that model F value is 70.64, which is more than 0.05, which shows that the selected model is significant.

Here talc concentration in sustained-release coating solution affects significantly agglomerates formation during the coating process. The value of adequate precision is 28.107, which means that model can be used to navigate the design space.

Statistical equation for the prediction of response Y₁ (Agglomerates) is: 0.1941+0.0354*A + 0.2475*B - 3.92*C-2.07*A*B - 0.2025*A*C - 0.3146*B*C + 0.2824*A² + 0.3324*B² + 2.83*C²

TABLE 11: ANOVA RESULT OF DEPENDENT PARAMETERS (Y₂: COATING PROCESS EFFICIENCY)

ANOVA results for coating process efficiency show that model F value is 25.94, which is more than 0.05, which shows that the selected model is significant. Here coating weight gain and talc concentration in sustained-release coating process were significantly influence coating process efficiency. The value of adequate precision is 14.003, which means that model can be used to navigate the design space.

Statistical equation for the prediction of response Y₂ (Coating process efficiency) is: 94.62 + 1.63*A + 1.27*B - 2.55*C + 1.63*A*B + 1.15*A*C + 1.55*B*C - 1.02*A² - 2.22*B² - 1.12*C²

TABLE 12: ANOVA RESULT OF DEPENDENT PARAMETERS (Y₃: DRUG RELEASE AT 1 h)

ANOVA analysis results for drug release at 1 h shows that model F value is 43.99, which is more than 0.05, which shows that the selected model is significant.

Here coating weight gain plays a significant role in drug release at 1 h. The value of adequate precision is 22.988, which means that model can be used to navigate the design space.

Statistical equation for the prediction of response Y₃ (Drug release at 1 h) is: 20.55-23.30*A - 1.98*B + 4.49*C + 1.32*A*B - 3.65*A*C - 5.07*B*C + 8.41*A² + 3.73*B² - 1.29*C²

TABLE 13: ANOVA RESULT OF DEPENDENT PARAMETERS (Y₄: DRUG RELEASE AT 4 h)

ANOVA results for drug release at 4 h shows that model F value is 478.13, which is more than 0.05, which shows that the selected model is significant.

Here coating weight gain and talc concentration both play a significant role in drug release at 4 h. The value of adequate precision is 74.262, which means that model can be used to navigate the design space.

Statistical equation for the prediction of response Y₄ (Drug release at 4 h) is: 45.73-26.13*A -1.31*B + 5.37*C + 4.65*A*B - 4.42*A*C - 2.95*B*C + 6.24*A² + 5.34*B² + 0.6132*C²

TABLE 14: ANOVA RESULT OF DEPENDENT PARAMETERS (Y₅: DRUG RELEASE AT 7 h)

For drug release at 7 h, ANOVA results show that model F value is 108.68, which is more than 0.05, which shows that the selected model is significant. Here coating weight gain imparts a significant role in drug release at 7 h. The value of adequate precision is 33.595, which means that model can be used to navigate the design space.

The statistical equation for the prediction of response Y₅ (Drug release at 7 h) is:

74.51 - 19.48*A -0.7071*B + 2.83*C + 4.18*A*B - 2.36*A*C + 1.62*B*C - 2.81*A² + 6.96*B² - 0.6897*C²

TABLE 15: ANOVA RESULT OF DEPENDENT PARAMETERS (Y₆: DRUG RELEASE AT 10 h)

ANOVA results for drug release at 10 h shows that model F value is 11.28, which is more than 0.05, which shows that the selected model is significant. Here coating weight gain plays a significant role in drug release at 10 h. The value of adequate precision is 9.955, which means that model can be used to navigate the design space.

The statistical equation for the prediction of response Y₆ (Drug release at 10 h) is:

99.23 - 11.84*A + 0.7778*B + 0.9546*C + 2.50*A*B - 2.22*A*C + 1.66*B*C - 9.29*A² - 1.91*B² - 0.9868*C²

The overall conclusion of ANOVA results was revealed that % weight gain and Talc concentration are more significant parameters that affect the responses understudied, i.e. (agglomerates, process efficiency, and drug release).

FIG. 2: OVERLAY COUNTER PLOT OF % COATING WEIGHT GAIN AND TEC CONCENTRATION RESPONSES STUDIED

FIG. 3: OVERLAY COUNTER PLOT OF % COATING WEIGHT GAIN AND TALC CONCENTRATION ON RESPONSES STUDIED

FIG. 4: OVERLAY COUNTER PLOT OF TEC AND TALC CONCENTRATION ON RESPONSES STUDIED

Yellow color area-design space in depicted overlay plot yield desired parameter settings for which all dependent responses will always be within the accepted level.

CONCLUSION: Based on this research work, it was concluded that sustained-release coated pellets were successfully developed for dexketoprofen trometamol drug-using kollicoat SR 30D as a ready-mix polymer with triethyl citrate as plasticizer and talc as an anti-tacking agent. Wurster coating process yields uniform and narrow particle size distribution range pellets. Yellow zone in overlay plot gives appropriate formulation components level setting, which will give robust pellets formulation having desired quality attributes.

ACKNOWLEDGEMENT: The authors are thankful to Emcure Pharmaceuticals Limited for their support in this research work.

CONFLICTS OF INTEREST: We authors, the undersigned research article entitled “Sustained Release Multi-particulates Formulation of a stereo-selective molecule of Ketoprofen by fluid bed processor” confirm that we do not have any conflict of interest in connection to the proposed research work.

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    How to cite this article:

    Prajapati BG and Patel A: Sustained release multi-particulates formulation of stereo-selective molecule of ketoprofen by fluid bed processor. Int J Pharm Sci & Res 2020; 11(9): 4359-69. doi: 10.13040/IJPSR.0975-8232.11(9).4359-69.

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