PRONIOSOMES-ENCAPSULATED DEXKETOPROFEN TROMETAMOL, FORMULATION, OPTIMIZATION, CHARACTERIZATION WITH IMPROVED DRUG RELEASE

PRONIOSOMES-ENCAPSULATED DEXKETOPROFEN TROMETAMOL, FORMULATION, OPTIMIZATION, CHARACTERIZATION WITH IMPROVED DRUG RELEASE

Tanu Bhargava * and Kamlesh Dashora

Institute of Pharmacy, Vikram University, Ujjain, Madhya Pradesh, India.

ABSTRACT: Photodermatitis had been defined within the literature after using oral dexketoprofen and different facet results as NSAIDs are also harmful for the liver. So, to triumph over such risky results, this molecule has been encapsulated with the assistance of non-ionic surfactants. Current studies supported the occasion and differentiation of transdermal proniosome-primarily based gel. The preformulation observation was completed through FTIR, and the assessment of the method through diverse parameters like PDI, zeta capacity, drug launch, encapsulation performance, and drug content material for the formulations Dt1-Dt9. The changed proniosomal gel suggests desirable balance, launch, following 0 order kinetics; most zeta strength is ± 49mv. The drug content material in the method turned inside an envisioned variety of 92-97%. The composition of the gel might be looked after as follows in relation to the viscosity of the drug: Dt3> Dt2> Dt9> Dt7> Dt4> Market gel> Dt6> Dt5> Dt1> Dt8. Span 40 & span 60 (50:50) proniosomal gel confirmed a drug launch as much as 12 h. The encapsulation performance of proniosomal gel formation levels from 82.10% to 94.12%. Proniosomal transdermal gels had been satisfactorily developed, FTIR observe suggests no large drug excipient interaction, drug launch profile follows zero-order kinetics. The parameter results show that optimized components dt9 & the organized proniosomes have fantastic service for dexketoprofen trometamol drug delivery.

Keywords: Coacervation section separation approach, Proniosomes, Zeta capacity, Poly dispersibility, Balance, Permeation

INTRODUCTION: Proniosomes is a type of water-soluble service debris that can be coated with a surfactant when dry. They are immediately rehydrated to form niosomal dispersion before being used on agitation in a warm aqueous solution. Proniosomes remain bodily solid during storage and transportation.

Drugs encased in the vesicular structure of proniosomes have a longer life within the systemic flow, augment penetration into the target tissue and reduce harmful side effects. Proniosomes have been investigated as an alternative to lipid vesicles as a drug carrier and various service architectures for entrapping both polar and nonpolar, as well as hydrophobic and hydrophilic pharmaceuticals.

The extra deserves with proniosomes are low toxicity due to non-ionic nature, no requirement of unique precautions and situations for method and preparations. In addition, it's far the easy approach for the recurring and huge scale manufacturing of proniosomes without using unwanted solvents.

However, balance is a first-rate issue withinside the development of any method, or even proniosomes have benefits as drug carriers, consisting of price productivity, chemically balance in comparison to liposomes. They also reduce bodily balance troubles consisting of fusion, leakage, sedimentation and aggregation in the garage. The benefits of dry niosomes, commonly termed as proniosomes have made them a promising commercial product ¹.

Dexketoprofen is a nonsteroidal anti-inflammatory medication that is derived from aryl propionic acid (NSAID). It's the dextrorotatory enantiomer of ketoprofen, a common nonsteroidal anti-inflammatory drug. Ketoprofen has been used since 1973 and has anti-inflammatory, analgesic, and antipyretic properties. In-vitro, racemic ketoprofen inhibits prostaglandin production effectively. The (S) - (+) - enantiomer (dexketoprofen) is responsible for the end result, whereas the (R) - (-) - enantiomer lacks organic activity. Dexketoprofen trometamol is suggested to deal with mild-to-slight ache situations consisting of musculoskeletal ache (osteoarthritis, low returned ache), dysmenorrhoeal & dental aching.

The parenteral method is indicated for the symptomatic remedy of the acute ache of slight to-intense intensity, while oral management isn't appropriate, consisting of postoperative ache, renal colic, and occasional returned dull pain ⁹. Oral remedy of Dexketoprofen could be very effective; however the medical use is regularly restrained due to the unfavourable results consisting of Photodermatitis, infection and ulceration of the gastrointestinal tract. Dexketoprofen possesses decrease molecular weight (375.4) and relatively quick half-life (1.65 h) in plasma and has the capacity to be introduced topically. Transdermal drug delivery has been taken into consideration to be the perfect path for dexketoprofen management. Therefore, the prevailing observation turned toward optimizing dexketoprofen proniosomes for favored reaction observed through in-vitro assessment after embedding the proniosome.

MATERIALS AND METHODS: Emcure Pharmaceuticals Ltd. Gandhinagar, Gujrat, India, provided dexketoprofen trometamol as a given sample.

Pre-formulation Research The purpose of the preformulation study was to ensure the accuracy of the drug sample and to determine various parameters for the formulation of proniosomal transdermal gel.

Identification of Drug: Organoleptic attributes Color, aroma and taste were investigated as part of the drug's organoleptic qualities ³.

Determination of λ_max: Dexketoprofen trometamol (100mg) with the correct weight was mixed in 100 ml of 0.1N HCL solution (1000μg / ml), (1 ml) aliquots from the answer are extracted in 10 ml volume bottles and thus concentration (100μg) / ml). And 1 ml of aliquots was dispensed up to 10 ml (10μg / ml) and scanned to get high absorption employing a double beam U.V. visible spectrophotometer at a distance from 200 to 600 nm ^4-8.

Construction of Ordinary Calibration Curve of Dexketoprofen:  The quality solution was prepared by dissolving 100 mg of Dexketoprofen trometamol in phosphate buffer of pH 7.4 during a 100 ml volumetric flask, and volume was made up to mark with the media. Subsequently, the quality solution was diluted with the medium to get a series of dilutions containing 2, 4, 6, 8, and 10 µg/ml of solution. The absorbance of those dilutions was measured using UV spectrophotometer (Shimadzu, UV-) at 260 nm against the phosphate buffer of pH 7.4 as a blank 4^-8.

Identification of Pure Drug by Fourier Transform Infrared Spectroscopy: FTIR Spectroscopy is done by using Shimadzu (8400S) by salt (KBr) pellet method within the wavelength range of 4000-1 and 400 cm^-1.

Drug- excipient Compatibility Studies: Method 1 a little amount of the drug, i.e., the body mixture of the drug and also the auxiliary substances (in a ratio of 1: 1 was prepared for a possible interaction) was placed in an exceeding bottle, and a rubber lid was placed within the bottle & is fit closed. The ultimate time was 2 weeks at 60 °C , and also the same sample was kept for two months at 40 ° C. After storage, the sample was physically checked for liquefaction, caking, odor or gas formation, and variability. Method 2, the apparent mixture of drug and auxiliary agents, was analyzed by FTIR spectroscopy.

Formulation: Proniosomal gels are performed in an exceedingly way that separates the coacervation phase. Accurately measured amounts of dexketoprofen trometamol, non-ionic surfactants, soy lecithin and cholesterol were taken from a glass bottle with a good clean and waterlessness containing ethanol 2.5 ml. The open area of the bottle was covered with a lid to avoid loss of solvent and heated to 65 ± 3 ° C until the surfactant mixture was completely dissolved. Then 1.8 ml of phosphate buffer pH 7.4 (liquid phase) was added to the surface and heated to get an equal scattering. Cooling was then allowed until the dispersion was converted to proniosomal gel.

The improved construction was compared to the merchandise on the market. Nine styles of dexketoprofen trometamol were developed and described as Dt1 to Dt9, respectively. The composition of gels is listed in Table 1.

TABLE 1:  COMPOSITION OF THE PRONIOSOMAL TRANSDERMAL GEL FORMULATION

Gel Evaluation Methods:

pH Measurement: By digital pH meter all nine formulations of transdermal proniosomal gel of dexketoprofen was measured.

The Drug Content: In 50 ml of methanol, one gram gel was dissolved. The resulting solution was mass transferred to volume flasks, and purification was performed with phosphate buffer pH 7.4 and analyzed the content of dexketoprofen trometamol at 260 nm with UV-spectrophotometer ^4-8.

Rheological Studies:

Viscosity: For non-Newtonian fluids like gel we use multiple points of viscometer so here, Brookfield digital viscometer (DV-I + model) was used to measure the viscosity (in cps). Spindle no.90 was rotated at 7 rpm. The composition viscosity was superb which was near 100% torque. Samples were rated at 36 ± 10 C. The reading was obtained 36 seconds after the measurement was performed, at which point the extent was stabilized.

Spreading: Concentrated circles of various radii were drawn on paper, and a glass plate was placed on that. The gel (25.0 gm) is transferred to the middle of the lower plate. A 100 ± 5 gm glass plate was gently located within the gel, and also the distribution width was recorded after 1 minute of each addition. In-vitro release studies of the proniosomal transdermal gel of dexketoprofen trometamol for in-vitro release as a receptor, phosphate buffer pH 7.4 was utilized.

In the Franz cell distribution, the premade membrane was used. A gel sample was applied to the membrane, which was subsequently placed in the distribution cell between the donor and receiver.

A phosphate repository with a pH of 7.4 is found in the receptor component. The temperature of the diffusion medium was thermostatically controlled at 37°C and activated by a magnetic stirrer spinning at 100 rpm. At predefined periods, the material was spectrophotometrically analyzed at 260nm using a phosphate bath pH 7.4 as a solvent ⁸.

For drug encapsulation efficiency purposes in an extremely glass tube, a proniosomal gel of Dexketoprofen trometamol (0.2 g) was reconstituted with 10 ml of phosphate buffer of pH 7.4 and centrifuged at 15000 rpm for 90 minutes at 25°C. The free drug absorption inside the resultant solution was measured using a UV spectroscopic technique at 260 nm after the supernatant was collected and diluted with phosphate buffer of pH 7.4.

The following equation was used to calculate the proportion of drug encapsulation.

EP (%) = [(ct - cr)/ct] × 100

(EP) is that the encapsulation proportion, (Ct) is the concentration of total drug and (Cr) is the concentration of the free drug. Trans-mission microscopy (TEM) Morphology and, therefore the structure of the prepared proniosomal gel was examined using a microscope to transmit high clarity, MAKE: JEOL, MODEL: JEM 2100 plus. A well-developed proniosomal gel (dt9) was tested ⁶.

Stability Studies: The construction was maintained at 4°C, 25°C, and 45 °C for 45 days and was tested with the following parameters ^4-8.

Physical Stability: The composition of the gel was assessed by visual characteristics such as phase separation and color change, odor, and rheological parameters.

Chemical Stability: The medication concentration of the gel formulations was assessed, as well as the separation of liquid exudates.

RESULTS:

Preformulation Studies:

Identification of Drug:

Organoleptic Properties: Organoleptic properties of the drug were found within limits, as shown in Table 2.

TABLE 2: ORGANOLEPTIC PROPERTIES OF THE DRUG

Determination of λ_max: Maximum absorbance of the drug was found at 260 nm, as shown in Fig. 1.

FIG. 1: λ_MAX OF DEXKETOPROFEN TROMETAMOL

Standard Calibration Curve of Dexketoprofen: Standard calibration curve was constructed using MS Excel, as shown in Fig. 2 & Table 3.

TABLE 3: DEXKETOPROFEN CONCENTRATION VS. ABSORBANCE IN PHOSPHATE BUFFER pH 7.4

FIG. 2: STANDARD CURVE OF DEXKETOPROFEN TROMETAMOL

Identification of Pure Drug by Fourier Transform Infrared Spectroscopy Fig. 3: Results shows compliance of structure of drug. Observed Carbonyl groups between 1770 cm^-1 and 1750 cm^-1 with strong bands may be recognized to the stretch vibration of the carbonyl groups present in the two monomers. Medium intensity bands between 1300 cm^-1 and 1150 cm^-1 show asymmetric and symmetric streches C-C(=O)-O, respectively, esters are identified by distinctive bands. “According to the literature, confirmation of dexketoprofen by an strong band at (1536 cm⁻¹), 1020 cm⁻¹), (771 cm⁻¹)  ‘at (1571 cm⁻¹), (1020 cm⁻¹), (881 cm⁻¹) & (641cm⁻¹), Vibrations indicate the purity of dexketoprofen we concluded that functional group are represents in this IR that the given drug are pure and identical ¹⁰.

FIG. 3: FTIR SPECTRA OF PURE DRUG DEXKETOPROFEN TROMETAMOL

Drug-Excipient Compatibility Studies: The results of Drug-Excipient Compatibility studies suggest drug and excipients' stability.

Dexketoprofen trometamol and all excipients are stable and accepted. A spectrum of dexketoprofen trometamol and its physical mixtures with excipients are revealed in Fig. 4. The FTIR spectrum analysis revealed a shift in % transmittance, which might be attributed to crystallinity changes, but no removal of any of the pure drug Dexketoprofen trometamol's distinctive peaks in the physical mixing of drug to polymer.

This eliminates the possibility of a drug-polymer compound interaction.

FIG. 4: FTIR SPECTRA OF PHYSICAL MIXTURE OF PURE DRUG AND EXCIPIENT

Results of Evaluation of Proniosomal Trans-dermal Gel: Measurement of pH All formulations had a pH close to that of the skin, as shown in Table 4, indicating that there was no danger of skin irritation and that they were superior to the marketed formulation due to their neutral pH.

TABLE 4: FORMULATION'S pH

Drug Content: The drug content in each sample was determined by using the standard calibration curve.

The percent drug content of all formulations and marketed preparation was shown in Table 5; the drug content values of the formulations were well within the range of 92-97 %.

TABLE 5: DRUG CONTENT OF DIFFERENT FORMULATIONS

Rheological Studies: Non-Newtonian (plastic flow) was seen in all gels. The gel compositions were found to have good spreadability and viscosity.

Viscosity Study: Table 6 shows Gel formulations can be graded in the following order concerning the viscosity of the drug: Dt3> Dt2> Dt9> Dt7> Dt4> Marketed gel> Dt6> Dt5> Dt1> Dt8.

TABLE 6: VISCOSITY OF DIFFERENT FORMULATIONS

Spreadability: The spreading area was plotted as a function of the applied mass in the results. Gel weight: 25 gram Compared to the marketed gel, the spreadability of formulations Dt9 and Dt7 containing Dexketoprofen trometamol gel was good.

TABLE 7: SPREADABILITY OF DIFFERENT FORMULATIONS

In-vitro Release Studies of Proniosomal Transdermal Gel of Dexketoprofen Trometamol: Table 8 Fig. 5 shows the findings of the in-vitro diffusion research over the egg membrane using different gels. The diffusion profile follows zero-order kinetics, as evidenced by the correlation coefficient values (r). In terms of the rates of release of Dexketoprofen trometamol from the gel formulations, they can be graded in the following order: Dt9>Dt8> Dt10> Dt6> Dt7, > Dt1, > Dt3, > Dt2.> Dt5.> Dt4. Dt9>Dt8> Dt10> Dt6> Dt7, > Dt1, > Dt3, > Dt2.> Dt5.> Dt4. The permeation profile revealed that formulation Dt9, which contained a span 40 and spanned 60 proniosomal gel in a 50:50 ratio, provided the best drug release for up to 12 hours. The Dt9 formulation was shown to have superior penetration and hence might be evaluated as a possibility for topical dosage form development.

FIG 5: PERCENT DRUG RELEASE

TABLE 8: STUDY OF IN-VITRO RELEASE IN PBS 7.4 pH

TABLE 9: RELEASE KINETICS OF PRONIOSOMAL GELS

Drug Encapsulation Efficiency Determination: Proniosomal gel formulations had encapsulation efficiency ranging from 82.10 percent to 94.12 percent. Table 10 shows the drug encapsulation efficiency of nine formulations.

TABLE 10: ENCAPSULATION EFFICIENCY OF DIFFERENT FORMULATION

Transmission Electron Microscopy (TEM): HRTEM showed that the particles have circular, uniform shapes. The dense, well-distributed pattern observed in Fig. 6 in the electron micrographs of dt9, Transmission reveals the structure of hydrated niosomal vesicles that are well-defined. The niosomes are unilamellar vesicles, spherical, nano-size, with sharp and well-separated limits.

FIG. 6: HRTEM ANALYSIS

FIG. 7: SURFACE MORPHOLOGY BY OPTICAL MICROSCOPE

Particle Size, Zeta Potential & Polydispersibility Index: Analysis of the proniosome-based niosome particle size shows that the SD (nm) particle size is 209.5 nm with a polydispersity index of 0.182.

The zeta strength of the prepared structure shown in Fig. 8 dt9 obtained within a range of 49.02 shows good stability of proniosomal gel.

FIG. 8: ZETA POTENTIAL

Stability Studies: There was no change in colour, odour, drug content, rheological properties, pH, or phase separation during 45 days at varied temperature conditions (4°C, 25°C, and 45°C) reported in Table 11, as there was no change in colour, odour, drug content, rheological properties, pH, or phase separation. As a result, it's possible to establish that formulation (Dt9) was chemically and physically stable.

TABLE 11: ACCELERATED STABILITY STUDIES OF FORMULATION

DISCUSSION: The dexketoprofen trometamol transdermal proniosomal gel was formulated, and all formulations were prepared for drug content, encapsulation efficiency, stability, dispersion, viscosity, pH & excipient interactions of the drug were examined are the most suitable formulas are containing span 40 and span 60 in equal measure among all species. The pH of the entire composition was about 7.11 to 7.20, indicating that there was no skin irritation. The active medication content ranged from 92 to 97 percent. In terms of drug viscosity, the gel's composition can be categorised as follows: Dt3> Dt2> Dt9> Dt7> Dt4> Gel Market> Dt6> Dt5> Dt1> Dt8. Dt3> Dt2> Dt9> Dt7> Dt4> Gel Market> Dt6> Dt5> Dt1> Dt8. In comparison to the gel on the market, the prevalence of Dt9 formulations, including Dexketoprofen trometamol gel was good. The correlation coefficients (r) values suggested that the distribution profile followed zero-order kinetics. In terms of Dexketoprofen trometamol release levels, the gel's components can be organized in the following order: Dt9> Dt8> Dt10> Dt6> Dt7,> Dt1,> Dt3,> Dt2.> Dt5.> Dt4.

From the permeation profile, it was clear that the Dt9 formulation containing span 40 & span 60 (50:50) proniosomal gel showed a drug release up to 12 h. The structure of Dt9 has been found to have better penetration and can be considered a candidate for the development of volume capacity forms. The encapsulation of drug in proniosomal gel formation ranges from 82.10% to 94.12%

CONCLUSION: Prepared formulations of dexketoprofen trometamol gel using surfactant span 40 and span 60 and cholesterol used as stabilizer & to improve penetration lecithin i.e from soya is used. Drug excipient compatibility was known through FTIR. Vesicle analysis was carried out through HRTEM. By finally carrying out different evaluation parameters, dt9 was found as the optimized formulation. The entrapment efficiency of dt9 was 94.12 as the surfactant and lecithin are increased, and the drug release is also increased to a certain extent. The release kinetics was calculated and the best fit order is zero-order and the Higuchi mechanism. These carrier systems have broad scope in the future, especially in transdermal drug delivery. This work will provide the benefits of controlled and sustained release activity, stability and versatility as a drug transporter, formulation with improved physical and chemical stability, and good bioavailability for a low soluble drug. This Proniosomal gel makes a significant contribution to the development of transdermal research and offers hope for the development of a successful transdermal system that will be of value to society, industries and academy.

Recommendation: Further in-vivo have a look at having to be performed to make certain pharmacological hobby and appropriate techniques as drug delivery for transdermal purposes. The Source of funding this have a look at has now no longer acquired any unique investment from any public, commercial, or nonprofit investment agency.

Ethical Approval: there is no requirement for ethical Approval in this research.

Authors' Contributions: TB designed, carried out the formula have a look at carried out the pre-formula have a look at & Drafted the manuscript. KD supervised it.

ACKNOWLEDGMENT: We are grateful for the pattern from emcure drugs ltd. Gandhinagar, Gujarat, INDIA, For the studies, look at Punjab college Research Centre in Chandigarh, India; IISER Bhopal, India.

CONFLICT OF INTEREST: The authors haven't any struggle of hobby to claim. The authors claim that they have got no acknowledged competing monetary hobbies or private relationships that would have been regarded to persuade the paintings said in this paper.

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    How to cite this article:

    Bhargava T and Dashora K: Proniosomes-encapsulated dexketoprofen trometamol, formulation, optimization, characterization with improved drug release. Int J Pharm Sci & Res 2022; 13(9): 3658-67. doi: 10.13040/IJPSR.0975-8232.13(9).3658-67.

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