Effect of combination of some Polymers with Carbopol 940 on Pregabalin Release Rate from Emulgels

 

Nawar Haddad, Jameela Hasian

Department of Pharmaceutics and Pharmaceutical Technology, Damascus University, Syria.

 

ABSTRACT:

Topical Emulgels of Pregabalin were formulated using Carbopol 940 in combination with (PVP k90, PEG 200, PEG 1000, HPMC K15M) to obtain the optimal formula in terms of drug release rate. Physical appearance, pH, viscosity, stability, drug content, In-vitro drug release, Differential scanning calorimetry and Fourier transform infrared spectroscopy, were tested in all formulas and evaluated to determine the best one. All formulations had good physical properties and stability, F2 which contains Carbopol 940 0.4% and HPMC K15M 0.4% gave the best drug release rate: (30% in 20 min and 93% in 360 min). But F3 which contains Carbopol 940 0.4% and PEG 200 10% showed the less release rate at 360 min: (64%). F2 showed Korsmeyer–Peppas model Kinetic release. So F2 was the best formula because it released drug since 10 min and still to 360 min (6 hours), thus F2 can be used to obtain rapid analgesic effect and avoid CNS-mediated side effects of Pregabalin.

 

 

 

INTRODUCTION:

Topical drug delivery system TDDS became a good therapeutic choice for many cases such as chronic pain management^1–3, anti-viral drugs⁴, anti-inflammatory drugs⁵, anti-arthritic⁶, antioxidants⁷, antimicrobial agents⁸, angina, congestive heart failure, and hormone replacement therapies⁹.

 

TDDS has several advantages such as ability to deliver drug more selectively to a specific site, avoid first pass effects, avoidance of gastro-intestinal irritation and metabolic degradation associated with oral administration^10,11, Having a therapeutic concentration of drug locally with low systemic drug levels¹² so it enhances the local and minimizes the systemic effects¹³, provide continuous drug administration, minimizing peaks and troughs in plasma levels throughout the day, useful for drugs with short biological half-lives requiring frequent oral or parenteral administration¹⁴, as well as it is non-invasive thus improving regimen compliance⁹.

 

Since 1980s, Emulgels became an important topical dosage form as one of Topical drug delivery system TDDS, Emulgels are emulsion either water-in-oil or oil-in-water type, which are gelled by mixing with a gelling agent¹⁵. Emulgels combine the advantages of emulsions and gels, Emulsion is a controlled release system, when drug particles are entrapped in the internal phase that slowly releases drug in a controlled way through the external phase to the skin to get absorbed¹⁶. Gel forms cross linked network where it captures small drug particles and provides its release in a controlled manner¹⁷.

 

Emulgel has favorable properties such as being thixotropic (reversible gel-sol-gel conversion induced by temperature, pH, or stirring) which improves stability and bioavailability of system^18,19, greaseless, easily spreadable, easily removable, emollient, pleasing appearance¹⁵, better stability comparing to other topical formulations such as creams and ointments²⁰, low ingredients and preparation cost, does not require any specialized instruments or intensive sonication, it is a good vehicle for hydrophobic or poorly water-soluble drugs as oil-in-water system entraps hydrophobic drugs in the oil phase.²¹

 

There are various methods of Emulgel formulation: the most common method is to prepare emulsion either (o/w or w/o) and prepare gel base, then mixing them in 1:1 ratio with gentle stirring to obtain Emulgel^3,4,22–27. Dispersing gelling agent (Carbopol) in oily phase, then adding the oily phase slowly to the aqueous phase with mixing, then gellifying the system by adjusting pH, and/or dispersing hydroxylpropyl methyl-cellulose²⁸. Dispersing gelling agent (Carbopol) in aqueous phase, then adding oily phase to aqueous phase with continuous stirring , then adjusting pH^29,30. Dispersing gelling agent (Carbopol) in aqueous phase, then adding the oily phase slowly to the aqueous phase with mixing³¹.

 

Pregabalin, an anti-epileptic drug³², is widely used for treatment of diabetic peripheral neuropathy, post-herpetic neuralgia, spinal cord injury nerve pain, and fibromyalgia^33,34. Pregabalin-treated patients had common mediated side effects on central nervous system such as dizziness and somnolence are common in Pregabalin-treated patients^35,36. Therefore, Topical application through the transdermal route is a possible option to reduce systemic drug exposure and penetration into the brain, and thereby to minimize CNS-mediated side effects. Pregabalin is sparingly soluble in water³⁷, it has Log P=1.116³⁸ and MW=159.23 Dalton³⁹.

 

In the present work, inclusion of Pregabalin in Emulgel dosage form may enhance penetration of Pregabalin into the skin and give rapid pain relief, in addition to Emulgel favorable properties mentioned previously. There are many reported Pregabalin formulations including nano-based hydrogel⁴⁰, Pregabalin patch⁴¹, and Pregabalin solution⁴².

 

The aim of this study is to prepare Pregabalin Emulgel formulations using Carbopol 940 as a gelling agent, and study the effect of different water soluble polymers on drug release rate when combined with Carbopol 940.

 

MATERIAL AND METHODS:

Materials:

Pregabalin (Aalidhra Pharmachem Pvt.Ltd, Gujarat, India), Carbopol 940 (Libraw Pharma, New Delhi, India), Hydroxypropyl methylcellulose HPMC K15M (ChemPoint, Maastricht, Netherlands), Castor oil (Jiangxi Global Natural Spice Co.Ltd, China ), Tween 80, Span 80, Polyethylene glycol PEG 200 and Polyethylene glycol PEG 1000 were purchased from (Riedel-De HaenAgseelze-Hannover. Germany), Propylene glycol, Povidone PVP K90, Methyl paraben and Propyl paraben were purchased from (Sigma-Aldrich, Germany).

 

Instrumentation:

Spectrophotometer (UV-VIS)(T80 UV VIS Spectrophotometer, UK) , pH meter (pH 211, HANNA, Italy), Viscometer (MYR rotary viscometer VR 3000, Spain), centrifugation machine (Hermle Z200A Centrifuge, Germany), Differential scanning calorimetry (DSC131, SETARAM, France), Fourier transform infrared spectroscopy (Bruker IR, Germany), Microscope (OLYMPUS-BX40, Japan).

 

Preparation of Emulgels:

The oily phase of the emulsion was prepared by dissolving span 80 in castor oil while the aqueous phase was prepared by dissolving Pregabalin and tween 80 in distilled water, PEG was dissolved in water (formulation containing PEG), then dispersing Carbopol 940 with constant stirring at a moderate speed using magnetic stirring, Methyl and propyl parabens were dissolved in propylene glycol and mixed with the aqueous phase, Both the oily and aqueous phases were separately heated to 70–80°C, then the oily phase was added to the aqueous phase, with dispersing HPMC or PVP (formulation containing HPMC or PVP) with continuous stirring  (up to 1 hour), Then pH was adjusted to 5.5–6.5 using sodium hydroxide (NaOH).The composition of different formulations has been discussed in Table (1).

 

Table (1): prepared formulations containing Pregabalin 2% (w/w%)

 

Physical appearance:

The prepared Emulgel formulations were inspected visually for their color, homogeneity, and phase separation.

 

Measurement of pH:

The pH of Emulgel formulations was determined by using digital pH meter (PH 211, HANNA, Italy). One gram of Emulgel was dissolved in 100ml of distilled water and it was placed for two hours. The measurement of pH of each formulation was done in triplicate and average values were calculated.

Measurement of Viscosity:

The measurement of viscosity was done with MYR rotary viscometer VR 3000, Spain. The Emulgels were rotated at 1, 2, 3, 4, 6 and 10rpm using spindle no. 5. At each speed, the corresponding reading was noted. The viscosity of each sample was measured in triplicate and the average and standard deviation (±SD) were calculated.

 

Centrifugation test:

Centrifugation test was carried out by placing 2g of formulation, in the centrifuge tube and centrifuge for two runs of 10 min, at 5000rpm in centrifugation machine (Hermle Z200A Centrifuge, Germany). At the end of each cycle, tubes were investigated  optically and macroscopically for the presence of any possible phase separation⁴³.

 

Drug content determination:

1g of Pregabalin Emulgel was taken and dissolved in 100 ml of distilled water. The volumetric flask were kept for 2 hours and shaken well in a shaker to mix it properly. The solution was passed through the filter paper 0.45μm and filtered. The drug content was measured spectrophotometrically at 475nm⁴⁴. All experimental processes was done in triplicate and average values were calculated

 

In-vitro drug release: ⁴⁵

Determination of prepared Emulgels In-vitro drug release was carried out using Franz diffusion cell, using synthetic cellulose nitrate membrane (Sartorius Stedim Biotech GmbH, Germany), Both compartments were clipped tightly to ensure no sample leaking. This provided an area of 2.54cm²  for the diffusion of Emulgel between the media. On top of the donor compartment was placed 300 mg of Pregabalin Emulgel, while the receptor compartment contained 9.5mL of distilled water. During the process, the temperature was maintained at 32±1°C and stirred at a speed of 650 rpm. At predetermined time intervals of 10, 20, 30, 45, 60, 120, 180, 240, 300, and 360min, 1 mL was taken out from the receptor compartment and another 1mL of distilled previously water heated to 32±1°C inserted into the same compartment as a replacement.

 

The 1 mL sample that was taken out from the receptor compartment was mixed with 1.5mL borate buffer pH=10.5 and 1mL of 1,2- naphthoquinone-4-sulphonate (NQS) solution in water (0.5% w/v), and heated for 10 min in water bath 50±5°C, then analyzed by ultraviolet spectrometry at wavelength 475nm⁴⁴. The collected data were analyzed with respect to percentage of cumulative Pregabalin detected in the receptor compart­ment. All experimental processes were carried out in triplicate and the average values were calculated.

From Fig (2): Concentration (μg/ml) = (absorbance-0.0359)/0.0247

Amount of drug released at time t (%) = Pt = concentration x dissolution bath volume x dilution factor x 100/ Dose (μg)

Cumulative percentage release (%) = Q% = Pt + P(t-1)x volume of sample withdrawn(ml)/bath volume(ml)

Where P(t-1)= percentage release previous to "t".

The equation become:

Q%=  (Absorbance -0.0359) 64.1 + 0.105 P(t-1)

 

Fig (1): absorption spectra of PG (25 μg mL^-1) with NQS.

 

Fig (2): Pregabalin titration line, with spectrophotometer at 475 nm.

 

Drug  Kinetic release:⁴⁶

Evaluation of kinetic release was carried out with respect to five kinetic models: zero-order, first-order, Higuchi, Korsmeyer–Peppas, and Hixson–Crowell. For each model, a graph was constructed based on the model’s theoretical equation, The best-fit equation was examined based on the coefficient of determination (R²) value gained from the plot­ted graph. Model equations used were:

zero-order (percentage of cumulative drug released versus time):

Q₀-Q_t=k₀t

 first-order (log percentage of cumulative drug remaining versus time):

Ln (Q₀-Q_t)= - k₁t

Higuchi model (percentage of cumula­tive drug released versus square root of time):

Q_t=kt^1/2

Korsmeyer–Peppas model (log percentage of cumulative cyclosporine released versus log time):

 

Q_t/Q_∞=kt_n

Hixson–Crowell model (cube root of drug remaining versus time):

 

Q₀^1/3-Qt^1/3=k_HC 

where Q₀ is the initial amount of Pregabalin in the sample, Q_t the amount of Pregabalin permeated, k₀ the zero-order rate constant, k₁ the first-order constant, k the constant reflecting the design variables of the system,

Q_t/Q_∞ the fraction of drug released over time, n the release exponent, k_HC the Hixson–Crowell rate constant, and t the time.

 

Differential scanning calorimetry (DSC):

A thermal analysis (DSC) of pure Pregabalin powder, pure excipients separately, the physical mixture (1:1) of Pregabalin with each excipient was performed with Differential scanning calorimeter (DSC-131,SETARAM, France). Samples were sealed in an aluminum pan and heated at a temperature range of 25–450 °C at the rate of 10°/min under a nitrogen atmosphere (Gas Flow: N2 - 100 ml/min).

 

Fourier transform infrared spectroscopy (FTIR):

Pure drug, pure excipients separately, the physical mixture (1:1) of Pregabalin with each excipient were characterized by FTIR. The IR absorption spectrum was taken in the range of 4000-400cm^-1 using (Bruker IR, Germany). The major peaks of Pregabalin spectrum were reported for evaluation of purity.

 

Statistical study:

One way ANOVA analysis was used to test the hypothesis that the means of several formulations In-vitro drug release are equal, the data were considered to be significant at p<0.05.

 

RESULTS AND DISCUSSION:

Physical appearance:

Table (2): Physical parameters of prepared Emulgels.

 

Measurement of PH:

All formulations had pH values between 6.02 and 6.5. The test was Performed in triplicates. The lowest pH value was 6.02 and was obtained from the Emulgel containing only Carbopol 940, while the highest pH value of 6.5 was obtained from Emulgel containing Carbopol 940 and PEG 1000.

Table (3):pH values of prepared formulations.

 

Measurement of Viscosity:

The viscosity (1 mPas=1 centipoise) of the different formulations was compared as shown in Fig (3), Viscosity was in the following order: F2>F1>F4>F5>F3, which were 74790>68920> 66432> 60505> 53579 mPas, respectively at 4 rpm.

 

These data indicated that the incorporation of HPMC to Carbopol 940 increases the viscosity.

 

All formulations showed decrease in viscosity as the shear rate is increased, this represents non-Newtonian system (shear thinning), because the viscosity changes according to the rate of shear¹⁸.

 

Figure (3): Effect of shearing on viscosity of  formulations F1–F5.

 

Centrifugation test:

The formulation showed good stability as no phase separation was observed when freshly prepared emulsion was studied under experimental conditions.

 

Drug content determination:

Emulgels prepared were containing Pregabalin that represents from 94% to 96% which is acceptable for all the formulations indicating uniform distribution of the drug and this complies with the requirements of U.S.P Pharmacopeia⁴⁷.

 

Table (4): Drug content in prepared formulations.

Formulation	Drug content%
F1	96
F2	96
F3	94
F4	95
F5	94

 

In-vitro drug release:

Drug release profiles of prepared Emulgels presented in Table (5). F2, F1 and F5 showed higher release rate of Pregabalin (93%), (92%) and (86%) respectively in 360 min. F3 and F4 showed less release rate (64%) and (76%) respectively.

 

Table (5): Cumulative amount of drug released %.

 

 

Drug Kinetic release:

Table (6) shows the coefficient of determination (R²) for every kinetic model studied. All the graphs showed linear relationships to different degrees. The highest R² value was produced by the Korsmeyer–Peppas model, followed by the Higuchi, Hixson–Crowell, zero-order, and first-order models. The best-fitted model was the Korsmeyer–Peppas model.

 

As Release Exponent (n)<0.5 Drug transport Mechanism is Quasi-Fickian diffusion i.e. Drug diffusion from non swellable matrix. Fickian diffusional release occurs by the usual molecular diffusion of the drug due to a chemical potential gradient⁴⁸.

Table (6): Drug Kinetic release.

 

Differential scanning calorimetry (DSC):

DSC technique was used to study the thermal behavior of Pregabalin and physical mixture of Pregabalin and excipients, to understand drug-excipient interactions.

Fig (4) shows DSC diagram of pure Pregabalin, a melting endothermic peak is observed on 198°C, which confirms the purity of drug substance.

 

Fig (4): DSC Diagram of Pregabalin.

 

DSC diagram of physical mixture of Pregabalin and carbopol 940 shows a broad endothermal peak is observed on 70°C indicates the evaporation of adsorbed water on carbopol 940, the melting peak of pregabalin appears with difference in the position of the peak on the temperature axis, aboat 14°C, that can be explained by drug-excipient interaction, and a broad endothermal peak is observed on 244°C at which decomposition of carbopol 940 begins.

 

DSC diagram of physical mixture of Pregabalin and HPMC K15M shows a broad endothermal peak is observed on 64°C indicates the evaporation of adsorbed water on HPMC, the melting peak of Pregabalin appears on 205°C with no great difference on the temperature axis, two broad endothermal peaks are observed on 239°C and 334°C that can be explained by  the beginning of HPMC decomposition. 

 

DSC diagram of physical mixture of Pregabalin and PVP K90 shows a broad endothermal peak is observed on 77°C indicates the evaporation of adsorbed water on PVP, the melting peak of Pregabalin appears on 202°C with no great difference on the temperature axis, two broad endothermal peaks are observed on 214°C and 430°C that can be explained by  the beginning of PVP decomposition. 

 

DSC diagram of physical mixture of Pregabalin and PEG 1000 shows  melting peak of PEG is observed on 37°C, the melting peak of pregabalin appears on 197°C with difference in the onset of the peak on the temperature axis, aboat 8°C, that can be explained by drug-excipient interaction, two broad endothermal peaks are observed on 277°C and 395°C that can be explained by  the beginning of PEG decomposition.

 

Fourier transform infrared spectroscopy (FTIR):

The drug excipients compatibility study was carried out by using FTIR. The FTIR spectral analysis of pure Pregabalin Fig (5) Showed the major peaks of functional groups of Pregabalin, Observed peaks are similar to reported peaks⁴⁹.

 

Fig (5): FTIR spectra of Pregabalin.

 

Table (7): Showing the major peaks of functional groups of Pregabalin obtained during FTIR.

Energy (Wave number) cm-1	Assignment
2954	0-H stretching
1643	C=O stretching
1544	N-H bending
1386	O-H bending , CH3 bending
1333	C-O stretching
1277	C-N stretching

 

FTIR spectra of physical mixture of Pregabalin and Carbopol 940 shows difference in the spectra of carboxylic acid and CH3 groups of Pregabalin is observed, i.e.  disappearance of three peaks (1386, 1333, 1277 cm^-1), difference in the position of the peak 1643 cm^-1 on the Wave number axis, and appearance of a new peak 1163 cm^-1, in addition to disappearance of two peaks that indicate Hydroxyl groups in Carbopol 940 (3678, 1238 cm^-1), these differences can be explained by formation of Hydrogen bonds between Pregabalin and Carbopol 940.

 

FTIR spectra of physical mixture of Pregabalin and HPMC K15M shows there is no chemical interaction between Pregabalin and HPMC because the major peaks of Pregabalin are retained with the excipient.

 

FTIR spectra of physical mixture of Pregabalin and PVP K90 shows there is no chemical interaction between Pregabalin and PVP because the major peaks of Pregabalin are retained with the excipient.

 

FTIR spectra of physical mixture of Pregabalin and PEG 1000 shows difference in the spectra of carboxylic acid and NH₂ group of Pregabalin is observed; i.e. disappearance of two peak (1643, 1544 cm^-1), difference in the position of the peak 2954 cm^-1 on the Wave number axis, in addition to disappearance of the peak that indicates C-H groups in PEG, these differences can be explained by formation of Hydrogen bonds between carboxylic acid and NH₂ groups of Pregabalin and PEG.

 

Statistical study:

One way ANOVA analysis of Emulgels In-vitro drug release showed that there is no Statistical significant difference between the means of prepared formulations, as  P-value= 0. 308>0.05.

 

CONCLUSION:

Topical Emulgels of Pregabalin were formulated using Carbopol 940 in combination with (PVP k90, PEG 200, PEG 1000, HPMC K15M) to obtain the optimal formula in terms of drug release rate.

 

All formulations had good physical properties and stability, In-vitro release study showed that the type of polymer affected the release rate, F2 which contains Carbopol 940 0.4% and HPMC K15M 0.4% gave the best drug release rate about 30% in 20 min and 93% in 360 min.

 

But F3 which contains Carbopol 9400.4% and PEG 200 10% showed the less release rate about 17% through 20 min and 64% in 360 min.

 

F2 and F3 showed Korsmeyer–Peppas model Kinetic release.

 

DSC and FTIR studies showed chemical interaction between Pregabalin and Carbopol 940, Pregabalin and PEG, that explains the prolonged drug release in formulations containing PEG 200 or PEG 1000, and that differs from results reported by Varma et al⁵⁰.  As there was no chemical interaction between Pregabalin and HPMC or PVP in  DSC and FTIR studies, they had no significant effect on release rate of the drug, and that differs from results reported by Tan et al⁵¹ , and agrees with Mohamed et al ²².

 

So F2 was the best formula because it released drug since 10 min and still to 360 min (6 hours), thus F2 can be used to obtain rapid analgesic effect and avoid CNS-mediated side effects of Pregabalin.

 

RECOMMENDATION:

Recommended for further In-vivo analgesic studies of F2. In addition to use Carbopol 940 in higher concentration with or without PEG to prepare extended-release topical formulations of Pregabalin.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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Received on 29.04.2021           Modified on 17.08.2021

Accepted on 27.10.2021         © RJPT All right reserved