Melt granulation for Enhanced Dissolution Rate and Antimicrobial activity of Cefpodoxime Proxetil

 

Nouran AbdelKader¹*, Amal Abo Kamer², Engy Elekhnawy², Mona Arafa¹,

Ebtessam A Essa¹, Gamal M El Maghraby¹

¹Department of Pharmaceutical Technology, Faculty of Pharmacy, Tanta University, Tanta, Tanta, Egypt.

²Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Tanta University, Tanta, Egypt.

 

ABSTRACT:

The aim of this work was to improve dissolution rate and antibacterial activity of cefpodoxime proxetil (CP) by Pluronic PE 6800 (Poloxamer 188) as eutectic forming hydrophilic polymer. CP was incorporated in the polymer by melt granulation technique. CP was mixed with melted polymer before addition of Avicel, in absence and presence of HPMC E6, with mixing to provide flowable particles. The formulations were characterized using thermal analysis and Fourier transform infrared spectroscopy (FTIR) in addition to dissolution studies. The antibacterial activity of CP against Proteus mirabilis was also explored. FTIR suggested possible hydrogen bonding between CP and polymers. All formulations improved CP dissolution compared to unprocessed CP. This could be attributed to the formation of eutectic species, as reflected by thermal analysis as new endothermic peak at T_m value of 40°C was detected in thermograms of all tested formulations. Microbiological investigations indicated that the optimized formulation offered advantages over pure CP with reduced minimum inhibitory concentration. Additionally, formulated CP decreased the biofilm formation ability among the tested P. mirabilis clinical isolates relative to unprocessed CP. The study introduced melt granulation of CP with poloxamer 188 as a promising tool for enhanced dissolution and augmented activity against Proteus mirabilis with capacity to minimize the biofilm formation.

 

 

 

INTRODUCTION: 

Cefpodoxime Proxetil (CP) is abroad spectrum, third generation β-lactam cephalosporin antimicrobial agent commonly used in the management of respiratory tract and urinary tract infections^1,2. CP is hydrolyzed to its parent effective moiety, cefpodoxime, by non-specific esterase enzymes during its permeation through the intestinal wall and in plasma³. CP is classified as Class IV (poorly soluble and poorly permeable) according to the biopharmaceutical classification system^4,5. CP is orally administered drug with biological half-life ranging from 2 to 3 hours⁶. The proxetil ester of the drug is designed to improve the absorption and consequently the bioavailability.

 

However, the degradation of the ester side group by cholinesterases in the intestinal lumen is another contributing factor for its low bioavailability (about 50%) following oral administration⁷. As a basic compound, CP shows a pH-dependent solubility that is being maximum at the acidic environment of the stomach and decreases as the pH value increases⁸. However, the gelation tendency of CP, especially in the acidic conditions, leads to erratic and slow dissolution^3,9.

 

Many approaches have been tried to enhance CP dissolution rate. These approaches include nanosuspension formation¹⁰, inclusion complexation¹¹, self-emulsifying drug delivery¹², solid lipid nanoparticles¹³, polymeric micro/nanoparticles¹⁴, amongst others^15,16.  Though various methodologies have been used to enhance solubility, dissolution rate and/or oral bioavailability of drugs with poor aqueous solubility, few studies employed the simple eutectic mixture formation.  This eutectic system is still under preliminary investigation regarding their pharmaceutical applications and not widely explored compared to solid dispersion and cocrystals, for example¹⁴.

 

This work was designed to improve CP dissolution rate employing solid dispersion technique,using Pluronic PE-68 (Poloxamer 188) as the solid matrix with possible eutaxia in mind. Melt granulation strategy was adopted. Pluronic PE-68 copolymer composed of two polyethylene oxide chains linked by a polypropylene oxide chain¹⁷. The Food and Drug Administration (FDA) has identified Pluronic PE-68 as a pharmaceutical additive, and it is commonly applied in pharmaceutical formulations due to its safety and commercial availability with reasonable price¹⁸. Pluronic PE-68 is expected to overcome the problem of poor solubility of CP by increasing its wettability and, therefore, decreases its hydrophobic nature. The effect of presence of Avicel (as a carrier), with or without hydroxypropyl methylcellulose E6 (HPMC E6), on CP dissolution rate was also explored. The antibacterial activity of the optimum formulation was tested against P. mirabilis isolates.

 

MATERIALS AND METHODS:

Materials:

Cefpodoxime Proxetil (CP) was a gift sample from Pharco Corporation, Egypt. Pluronic PE-68 (Poloxamer 188) was a gift sample from BASF, Germany. Avicel PH 102, Dupont, USA. HPMC E6 was a gift sample from Sigma Co., Qwesna, Egypt. All chemicals used in the microbiological studies were of pharmaceutical grade and they were purchased from Merck (USA). In addition, the utilized media were purchased from Oxoid (UK).

 

Methods:

Spectrophotometric assay of CP:

A stock solution of CP was prepared by dissolving 10 mg in 50 ml methanol (stock solution). Serial concentrations were prepared by transferring 2, 3, 4, 5, 6 and 7ml each into 50 ml volumetric flask and completing to volume using the dissolution medium (Glycine – sodium dihydrogen phosphate adjusted to pH 3). Agilent UV spectrophotometer was used in Absorbance mode at wavelength of maximum absorption 259 nm as stated by the USP monograph and as practically obtained by running the spectrum mode. The calibration curve was obtained by plotting the concentration versus absorption. The obtained plot was linear with R² value of 0.9987.

 

Preparation of CP hot melt granules:

CP microparticles were prepared by solid dispersion technique adopting hot melt congealing method^19,20. Solid dispersions were prepared using different mass ratios of CP and Pluronic PE-68, Avicel PH 102 and HPMC E6.

 

Table 1 shows the composition of all tested formulations. In a clean and dry porcelain dish, Pluronic PE-68 was heated up to 65^oC using water bath. After melting, the dish was set aside and the drug with other excipients, if present, were added with continuous mixing until congealing and formation of a homogenous solid mass. The mass was set aside till complete cooling and then grinded to form the microparticles, passed through 400µm sieve and maintained in a closed container until further use.

 

Characterization of CP granules:

Compatibility studies of CP with formulation additives:

Differential scanning calorimetry and Fourier transform infrared spectroscopy were performed to investigate any possible interaction between CP, Pluronic PE-68 and HPMC E6.

 

Differential scanning calorimetry (DSC):

These studies involved recording the thermal behavior of pure CP, Pluronic PE-68, HPMC E6 and the prepared formulations using DSC apparatus (DSC-60, Shimadzu, Japan). The instrument was calibrated with an indium standard.  Weights equivalent to approximately 5-7mg of each sample were loaded into aluminum pan and the lid was carefully closed using a Shimadzu crimper. The thermal events of each sample were  recorded under consistent increment in temperature starting from 25^oC through 400^oC at a heating rate of 10^oC/min. Data analysis was conducted using the TA-60WS thermal analysis software. The transition midpoint (Tm) of the drug was noted.

 

Fourier Transform infrared spectroscopy (FTIR):

FTIR spectra of CP, individual excipients and the prepared formulations were recorded using FTIR spectrophotometer (FTIR- Spectrometer, Tensor 27, Bruker, USA). Samples were mixed with potassium bromide (of spectroscopic grade) and compressed into compact disks using hydraulic press before scanning from 4000 to 600 cm^-1.

 

In vitro drug release studies:

The in vitro dissolution of CP from its pure state and its formulations were studied employing USP apparatus II (rotating paddle) dissolution tester apparatus (model DT820, Erweka, Germany). The dissolution medium consisted of 900ml Glycine–sodium dihydrogen phosphate adjusted to pH 3±0.1. From the prepared microparticle formulations, weights equivalent to 200mg of cefpodoxime were loaded to each dissolution vessel. A mass of 260mg of pure CP, equivalent to 200mg cefpodoxime, was used as control. The release studies were performed at 37±0.5°C, at a stirring rate of 75rpm for one hour. Samples (5ml each) were taken from the dissolution medium at pre-specified time scale and compensated by equal volume of fresh medium maintained at the same temperature. The samples were immediately filtered (0.45µm Millipore filter) and analyzed using UV spectrophotometer at 259nm for CP concentration. The amount of drug released at each time interval was determined and the cumulative amount of drug released was computed as a function of time to construct the dissolution profiles. The dissolution parameters were used to compare between different formulations. The similarity factor (f₂) test was employed to compare between the dissolution profiles. This employed the following equation:

 

where n is the number of the used data points, R_t is the amount released from the control (%) at time t, and T_t is the amount released of the test formula (expressed as percentage) at the same time²¹. Value of f2 equals to ore more than 50% means dissimilar dissolution data.

 

Table 1: The weight ratio of cefpodoxime proxetil (CP) and different excipients, together with the dissolution parameters.

	CP	Pluronic	Avicel	HPMC E6	Q5	Q60	DE(%)
PURE CP					10.5 ±1.5	27.4±5.2	18.7
F1	1	1	2		34.0 ±3.8	81.0 ±5.4	59.5
F2	1	0.5	1	1	13.7 ±1.0	62.9 ±3.7	38.6
F3	1	1	1	1	32.7 ±1.9	70.1±3.8	55.5
F4	1	1.5	1	1	57.4 ±3.3	100.3±2.1	79.7
PM	1	1.5	1	1	15.2±1.9	54.0±2.5	34.3

-Q5 and Q60 are the percentage cumulative amount of CP released after 5 and 60 minutes, respectively.

-DE is the dissolution efficiency expressed as percentage

 

Microbiological assay of CP:

The antibacterial and antibiofilm activity of the optimized hot melt microparticles (Formula F4), pure CP, pure Poloxamer 188 were investigated using Proteus mirabilis isolates.

 

Bacterial isolates:

Twenty-three P. mirabilis clinical isolates were obtained from patients admitting to Tanta university hospitals. The samples were taken from patients for routine medical investigations in the hospital and the patient data were obscured, so no ethical approval was required. The bacterial isolates were identified by standard microbiological tests²². Proteus mirabilis (ATCC 35659) was utilized as a reference isolate.

 

Susceptibility to CP, Pluronic PE-68, and its formulated form:

This was performed by disc agar diffusion method²³. Sterile filter paper discs were impregnated with 20µL of 1000µg/mL from each of CP, its formulated form (formula F4), and Pluronic PE-68 for preliminary screening of their antibacterial activity against P. mirabilis isolates. The bacterial suspensions (10⁸colony forming unite (CFU)/mL) were spread on the surface of Mueller-Hinton agar (MHA) using sterile cotton swabs. Then, the filter paper discs were placed individually on the surfaces of the MHA plates, and they were overnight incubated at 37°C. Ciprofloxacin was used as a positive control and dimethyl sulfoxide (DMSO) was used as a negative control.

 

Determination of minimum inhibitory concentration (MIC):

It was carried out by broth microdilution method in microtitration plates²³. A positive control (bacteria only) and a negative control (broth only) were included in each plate. The lowest concentration which gave rise to complete absence of bacterial growth was recorded as the MIC value.

 

Antibiofilm formation assay:

It was performed using crystal violet assay²⁴ before and after treatment with CP and its formulated form (at half MIC values) in 96 well microtitration plates. The optical density (OD) was measured at 490nm using an ELISA reader (Sunrise Tecan, Austria). Based on the measured OD values, P. mirabilis isolates were classified into four categories as follows:

 

Isolates not forming biofilms: (ODc < OD < 2 ODc)

Isolates weakly forming biofilm: (2 ODc < OD < 4 ODc)

Isolates moderately forming biofilm: (4 ODc < OD < 6 ODc)

Isolates strongly forming biofilm: (6 ODc < OD)

Cut-off OD (ODc) represents the mean of OD values plus three standard deviations (SD) of the negative control.

 

Examination of the antibiofilm activity using light microscope:

The antibiofilm effects of CP and its formulated form (F4) were examined using light microscope (Labomed, USA)²⁵. In brief, CP and F4 were incubated at their 0.5 MIC values with the tested bacterial isolates in Luria-Bertani (LB) broth in six-well microtitration plates overnight at 37°C. Then, the formed biofilms were stained using crystal violet (0.4%) and visualized by light microscope under a magnification of 100× and documented using a digital camera.

 

Statistical Analysis:

All experiments were conducted in triplicates and their results are demonstrated as mean ±SD. Student’s t-test was used for analysis of the dissolution studies. For microbiological assay, One-way ANOVA test (Graph pad Prism 8) was utilized followed by post-hoc test. Results were statistically significant when p values < 0.05.

 

RESULTS AND DISCUSSION:

Fourier Transform infrared spectroscopy:

FTIR was utilized to elucidate the possibility of interaction between CP and the utilized polymers. The recorded FTIR spectrums of pure cefpodoxime, Poloxamer 188 (Pluronic PE-68), HPMC and the prepared formulations are shown in Figure A. The FTIR spectrum of CP showed characteristic absorption bands which correspond to its main functional groups. The broad peak noted at 3350 cm^–1 is due to the NH stretching of the secondary amine. A fork-shaped band recorded at 2950cm^-1 can be accredited to NH₂ stretching with the peak at 1650 being attributed to N-H bending. The peaks that were observed at 1760, 1570 and 1112 cm^–1 are assigned for C=O, C=N and C-N stretching vibration, respectively. This spectrum with its absorption bands correlates well with the published data for CP^26,27.

 

The FTIR spectrum of pure Poloxamer 188 showed a broad absorption band at 3450 cm^–1 which is accredited to O-H stretching.  The strong absorption band observed at 2900 cm^–1 is due to aliphatic C-H bond. The C-O stretching vibration was observed as sharp peak at 1115 cm^–1. Similar peak assignments were published for Poloxamer 188²⁸.

 

The FTIR spectrum of pure HPMC E6 showed its characteristic peaks which include the broad peak at 3455 cm^–1 that corresponds to the hydroxyl group. The stretching vibration that was observed at 2900 is due to C-H group. This spectrum is similar to that reported by other investigators for HPMC²⁹. The FTIR spectra of the prepared formulations showed alterations in the main peaks compared with that recorded in pure CP or pure polymers. These alterations were manifested in the peaks recorded at 3350 and 2950 cm^-1 which were accredited to NH and NH₂ stretching vibrations (Figure A). These alterations may indicate possible hydrogen bond formation between the drug and the utilized polymers.

 

Differential scanning calorimetry (DSC):

Thermal analysis was conducted to assess potential interaction between CP and the used polymers. Figure 1B shows the recorded thermograms for pure CP, pure polymers and the prepared formulations. The thermogram of pure CP showed endothermic peak with an onset of 77.2°C, endset of 112°C and transition mid-point (T_m) of 97.7°C. This endothermic peak can be accredited to the melting of the drug and reflecting its crystalline condition. A broad exothermic peak was noted at T_m of 290°C with an onset of 230°C and endset of 232°C which can be attributed to drug degradation. This thermogram is comparable to that reported by other investigators^26,30.

 

Figure 1: Fourier Transform Infra-red spectroscopy (A) and differential scanning calorimetry (B) of unprocessed Cefpodoxime proxetil (CP), HPMC E6, Poloxamer 188 and different formulations. For detailed formulations are presented in Table 1.

 

The thermogram of pure Poloxamer 188 showed a sharp endothermic peak at 55°C which corresponds to its melting. Similar thermal behavior was reported in literatures^28,31. For HPMC E6, the thermal behavior reflected a broad endotherm that started at 60^oC and ended at 121.0^oC. This broad peak could be due to the evaporation of the adsorbed moisture. Another broad peak was recorded at T_m value of 360^oC and can be assigned to its degradation,1B. The same thermal pattern of HPMC was stated in previous research work^32,33.

 

The thermograms of the prepared granules showed remarkable change in the thermal pattern compared with pure CP and pure Poloxamer 188 (Figure 1B). The main endothermic peak of the drug and Poloxamer disappeared. This was accompanied with the appearance of new endothermic peak at T_m value of 40°C in all tested formulations. This new peak was recorded at lower T_m value compared with pure drug and pure Poloxamer which indicates possible formation of eutectic system. Similar explanations were reported previously in other research works^34–36. Another endothermic peak was recorded at 124°C which can be accredited to drug recrystallization. The recorded exothermic peak of the drug was shifted to higher T_m value which can be attributed to the decomposition of the recrystallized form of the drug. Similar thermal pattern was recorded for the formulations prepared using Poloxamer in presence of HPMC reflecting the absence of any impact of HPMC addition on the possibility of eutectic system formation between the drug and Poloxamer.

 

In vitro drug dissolution studies:

The dissolution profiles of pure CP and the prepared hot melt granules are shown in Figure 2. To compare between different samples, dissolution parameters were obtained from each dissolution plot and are presented in

Table 1. The selected comparative parameters were the percentage amount of CP released after 5 (Q5) and 60 minutes (Q60), and dissolution efficiency (DE). The DE was determined by calculating the area under the dissolution versus time curve at time, t (determined using the nonlinear trapezoidal rule) and expressed as a percentage of this area to that of the rectangle obtained assuming 100% dissolution occurs at the same time³⁷.

 

Pure CP showed a slow and erratic dissolution pattern with the release of about 10% of the loaded dose after 5 minutes. The total amount released after 60 minutes was only 24% of the loaded dose, with a dissolution efficiency (%) of 18.7. This poor dissolution can be accredited to the crystalline nature of CP as reflected by DSC data. Similar dissolution pattern was recorded by other investigators³⁸. This slow dissolution is not acceptable for formulations intended to immediate release purposes.

Solid dispersion using hydrophilic carriers have been always a beneficial pharmaceutical tool to improve the rate of dissolution and the therapeutic performance ofdrugs suffering from poor aqueous solubility³⁹. Poloxamer 188 was used as the hydrophilic inert matrix that was expected to improve CP wettability and/or self-assemble to encapsulate the hydrophobic drugs for enhancing dissolution of the poorly water-soluble CP. Addition of Avicel in the formulation aimed to provide a large surface area up on which the drug/surfactant system would deposit. This will have a dual benefit of obtaining a dry powder form with a large surface area. This can increase CP surface area with improved dissolution accordingly.

 

Formulation F1 (1:1:2 CP:PLX:Avicel, respectively) significantly improved CP dissolution compared to the unprocessed form (P < 0.05). There was about 3-fold enhancement in Q5 and DE ( Table 1). Such improved dissolution can be explained by the formed eutectic mixture between the matrix forming polymer and CP as evidenced by the DSC data. Development of eutectic systems with significant improved dissolution rate of drugs with poor solubility was previously reported³⁴. The superiority of eutectic mixture in enhancing CP dissolution was also indicated by the similarity value with f₂ value of 26%. Enhanced dissolution could also be due to the solubilizing effect from the highly soluble compounds in the eutectic couple i.e Poloxamer 188⁴⁰. Furtherly, the presence of Poloxamer as eutectic couple is expected to form micelles encapsulating the drug in a process known as micellization. These nanosized micelles are expected to improve paracellular and intracellular transports of CP after administration that would, consequently, improve its bioavailability.

 

One of the drawbacks of methods used to enhance dissolution by modulating the crystalline lattice of the drugs is their thermodynamic instability and the tendency of the drug molecules to crystallize out. Therefore, HPMC E6 was added as a fourth component in formulations F2 through F4 with the aim of minimizing recrystallization and/or crystal growth. HPMC E6 was previously reported to inhibit crystallization of amorphous solid dispersion⁴¹. As CP dose is 200mg, and to keep a reasonable size of the final dosage form, 50% of Avicel was replaced by HPMC E6 (Table 1). All granules (F2-F4) significantly improved dissolution pattern of CP compared to control (P < 0.05). The superiority of the prepared microparticles was further confirmed from the similarity factor with  f₂ values of 46, 29 and 16 for formulations F2, F3 and F4, respectively, when compared to pure CP. It was noticed that increasing Poloxamer concentration increased dissolution in the same rank.  Formula F4 showed the best dissolution parameters with 5.2-fold and 4-fold enhancement in Q5 and DE, respectively, compared to pure CP.

 

Figure 2: In vitro dissolution profiles of CP from unprocessed form and the prepared formulations. For detailed formulations are presented in Table 1.

 

To prove that the enhanced dissolution of CP is due to the adopted technique, the components of microparticles F4 were physically mixed (PM) using mortar and pestle, and the dissolution test was conducted under the same experimental conditions. PM showed similar dissolution pattern to pure CP, especially in the first 30 min of the test (Figure 2, Table 1). Though PM significantly (P<0.05) improved CP dissolution relative to pure PC, hot melt granules (formula F4) was superior to its physically mixed components with about 4-fold and 2.3-fold enhancement in Q5 and dissolution efficiency, respectively.

 

Antibacterial activity:

CP is an advanced-generation medicament used in the treatment of acute bacterial aggravation of chronic bronchitis, streptococcal pharyngotonsillitis and uncomplicated skin infections⁴². Proteus mirabilis is a Gram-negative bacterium which can cause various human infections like skin, eye, ear, gastrointestinal tract, and respiratory tract infections. It is commonly associated with urinary tract infections especially in patients having indwelling urinary catheterization⁴³. Antibiotic resistance is highly disseminating among these bacteria leading to an increase in the complications associated with the diseases they cause⁴⁴. In addition, they can form biofilm which help in the persistence of P. mirabilis in the human body via protection from the immune system and antibiotics⁴⁵. Thus, in the current study we determined the antibacterial and antibiofilm activity of pure CP, pure Poloxamer 188 and their formulation (F4) and form to find out a therapeutic alternative to infections caused by P. mirabilis.

 

Susceptibility to CP its formulated form, and poloxamer:

Owing to the dissemination of the antibiotic resistance among the pathogenic bacteria especially P. mirabilis isolates, a lot of efforts are being done to find out solutions to overcome this problem⁴⁶. Therefore, formulation of antibiotics to enhance their efficacy is an important approach that can be followed⁴⁷. Herein, we used disc agar diffusion method to investigate the antibacterial activity of CP, its formulated form (F4), and Poloxamer 188. We observed that both CP and its formulated form resulted in the formation of inhibition zones around the discs impregnated with them. On the other hand, Poloxamer 188 didn’t produce any inhibition zone which means that it doesn’t have antibacterial activity.Thus, the MIC values of CP and its formulated form were determined using broth microdilution method and the MIC values are shown in Table 2. Interestingly, the formulated CP form showed MIC values that were significantly lower (p< 0.05) than the MIC values of CP. MIC values are considered as a measure for the susceptibility or resistance of bacterial isolates to antimicrobial agents. Lower MIC values indicate that less antibiotic concentration is required for inhibition of the bacterial growth. Thus, antibacterial agents with lower MIC values are more effective against bacterial infections⁴⁸.

 

Table 2: MIC values of cefpodoxime proxetil (CP) and its formulated form against P. mirabilis isolates.

Isolate code	MIC of CP (µg/mL)	MIC of F4 (µg/mL)	Isolate code	MIC of CP (µg/mL)	MIC of the F4 (µg/mL)
Pr1	16	1	Pr13	8	2
Pr2	32	8	Pr14	64	4
Pr3	32	2	Pr15	16	2
Pr4	64	4	Pr16	16	2
Pr5	32	4	Pr17	64	4
Pr6	8	2	Pr18	64	8
Pr7	4	0.5	Pr19	128	16
Pr8	8	0.5	Pr20	128	8
Pr9	16	1	Pr21	32	2
Pr10	32	2	Pr22	8	1
Pr11	16	4	Pr23	16	0.5
Pr12	32	1

 

Antibiofilm activity:

Microorganisms can grow up either as planktonic (free-living) or embedded in biofilm. Biofilms are group of bacteria surrounded by a self-produced matrix. This matrix consists of polysaccharides in addition to proteins and DNA⁴⁹. Unfortunately, bacteria can acquire resistance to antimicrobials when they are embedded in the biofilm. This is mainly due to impairing the diffusion of the antimicrobials into the bacterial cells. Hence, compounds which have antibiofilm activity can decrease the development of antimicrobial resistance among the bacterial isolates⁵⁰. Crystal violet assay was utilized to investigate the antibiofilm effect of CP and its formulated form. It was found that the percentage of biofilm forming isolates (strong and moderate) decreased from 52.17% before treatment to 39.13% and 8.69 % after treatment with CP and its formulated form, respectively, as shown in.Table 3.

 

Table 3: Number of isolates which form biofilm before and after treatment with cefpodoxime proxetil (CP) and its formulated form.

Number of isolates based on ability of biofilm formation	Before treatment	After treatment with (CP)	After treatment with formula F4
Isolates not forming biofilms	3	4	8
Isolates weakly forming biofilm	8	10	13
Isolates moderately forming biofilm	7	5	1
Isolates strongly forming biofilm	5	4	1

 

Biofilm examination by light microscope:

The formed biofilm, before and after treatment with either CP or its formulated form, were examined using light microscope to study their effects on the biofilm morphology. As shown in Figure 3, a significant reduction in the biofilm formation was observed after treatment with the formulated form relative to that treated using pure PC.

 

Figure 3: An illustrative example for the biofilm formed by P. mirabilis isolate A) before treatment, B) after treatment with cefpodoxime proxetil, and C) after treatment with the formulated form

 

CONCLUSION:

Preparation of CP microparticles by melt congealing technique, using Poloxamer 188 as the solid matrix, markedly improved its dissolution. Presence of Avicel PH 102 and HPMC E6 were successful as carriers and stabilizers, respectively. The enhanced dissolution was due to the formation of eutectic mixture as reflected by DSC data. The optimized formulation offered advantages overpure CP as it significantly lowered its MIC values and decreased the biofilm formation ability among the tested P. mirabilis clinical isolates. However, this needs further studies to reveal the exact mechanism of action and to investigate its effectiveness in vivo.

 

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

 

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Accepted on 14.04.2023           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(8):3921-3928.