Description:1
FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE
SPECIFICATION
(See section 10 and rule 13)
NANOPARTICULATE DRUG DELIVERY SYSTEM FOR THE MANAGEMENT OF DIABETIC NEPHROPATHY
G D Goenka University, an Indian university of Sohna Gurugram Road,
Sohna, Haryana, India, 122103
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED
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FIELD OF INVENTION:
The present invention relates to pharmaceutical science field, which aims at design, development, and evaluation of a nanoparticulate drug delivery system for the management of diabetic nephropathy.
BACK GROUND:
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD) in developed countries, including the United States.[1] It is considered a microvascular complication and occurs in both diabetes mellitus type 1 (T1DM) and diabetes mellitus type 2 (T2DM). The disorder presents with persistent albuminuria and a progressive decline in the glomerular filtration rate. There is substantial evidence that early treatment can delay or prevent the progression of the disorder. The main microvascular consequence of diabetes mellitus (DM), diabetic nephropathy (DN), is what leads utmost to diabetic patients' greater risk of death. In the United States and most developed nations, diabetic nephropathy (30-50 %) is the main contributor to end-stage renal disease.
Telmisartan is used alone or together with other medicines to treat high blood pressure (hypertension). High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. Lowering blood pressure can reduce the risk of strokes and heart attacks.
Telmisartan is also used to lower the risk of heart attacks or stroke in patients 55 years of age and older who have diabetes or heart problems. Telmisartan is an angiotensin II receptor blocker (ARB). It works by blocking a substance in the body that causes blood vessels to tighten. As a result, telmisartan relaxes the blood vessels. This lowers blood pressure and increases the supply of blood and
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oxygen to the heart. Telmisartan (TLS) is a partial agonist of "peroxisome proliferator-activated receptor gamma (PPARc)" and an AT-1 receptor blocker.
Cilostazol is a quinolone derivative primarily used to treat intermittent claudication due to peripheral vascular disease, the FDA-approved indication. Cilostazol is also indicated for secondary prevention in patients with a history of transient ischemic attacks or non-cardioembolic ischaemic stroke. Cilostazol improves walking distance by promoting vasodilation and antiplatelet activity with inhibition of phosphodiesterase III and subsequent increases in available cAMP. This activity reviews the indications, contraindications, and use of cilostazol and highlights the role of the interprofessional team in monitoring the adverse effects of the drug. Cilostazol is a phosphodiesterase III (PDE3) inhibitor. PDE3s are enzymes that utilize a catalytic core to hydrolyze cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP). Phosphodiesterase III enzymes are primarily located within the cardiac sarcoplasmic reticulum and in the smooth muscle of arteries and veins, where they regulate cardiac and vascular smooth muscle contractility. Cilostazol exerts its action by inhibiting phosphodiesterase activity and suppressing cAMP degradation. The inhibition of PDE3 allows for a rise in cAMP in platelets and blood vessels. Increased concentrations of cAMP subsequently lead to increase concentrations of the active form of protein kinase A (PKA), and increased PKA is directly related to the inhibition of platelet aggregation. Elevated concentrations of intracellular PKA also elicit a vasodilatory effect on smooth muscle cells by preventing contraction through the inactivation of myosin light-chain kinase.
Chien-Wen Chian et al. 2020, showed that cilostazol (CTZ) can reduce ROS levels and decelerate DN progression in streptozotocin (STZ)-induced type 1 diabetes. Further investigated that the potential mechanisms of CTZ in rats with DN and in high glucose-treated mesangial cells. Male Sprague–Dawley rats were fed 5 mg/kg/day of CTZ after developing STZ-induced diabetes mellitus. Electron microscopy revealed that CTZ reduced the thickness of the glomerular basement membrane and improved mitochondrial morphology in mesangial cells of diabetic
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kidney. CTZ treatment reduced excessive kidney mitochondrial DNA copy numbers induced by hyperglycemia and interacted with the intrinsic pathway for regulating cell apoptosis as an antiapoptotic mechanism. In high-glucose-treated mesangial cells, CTZ reduced ROS production, altered the apoptotic status, and down-regulated transforming growth factor beta (TGF-ß) and nuclear factor kappa light chain enhancer of activated B cells (NF-?B). Base on the results of our previous and current studies, CTZ deceleration of hyperglycemia-induced DN is attributable to ROS reduction and thereby maintenance of the mitochondrial function and reduction in TGF-ß and NF-?B levels.
Nur Samsu et al., 2019, showed that treatment with RA (Rosmarininc acid) and TMS (Telmisartan) either monotherapy or in combination can inhibit the development and progression of DN. However, the combination of both did not show a synergistic effect, with even higher urinary albumin excretion and worse kidney function compared to the RA monotherapy. It is found that urinary level of podocin and nephrin, albumin urine excretion and serum cystatin C levels were significantly lower than the positive control group. Compared to negative controls, the group of treated diabetic rats did not differ significantly in preventing increased excretion of urinary nephrin and podocin. Meanwhile, treatment with RA monotherapy was significantly better than TMS or a combination of RA with TMS in reducing albumin excretion and preventing decreased kidney function.
Telmisartan (TLS) is a partial agonist of "peroxisome proliferator-activated receptor gamma (PPARc)" and an AT-1 receptor blocker also Curcumin (Cur) has been shown its antihyperglycemic properties, and both are water soluble and Cilostazol (CLT) is phosphodiesterase (PDE) inhibitor. It is also water-insoluble. Hence, Solid Nano dispersions were prepared as per the "Box-Behnken Design" using the emulsion solvent evaporation method to increase their bioavailability for both the drugs along with curcumin tagging individually.
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OBJECTIVE OF THE INVENTION:
1. It is an object of the invention to provide a method for preparing Cilostazol Solid Dispersion Nanoparticles (SND) with Thymoquinone (TLS) (80 mg) and Curcumin tag.
2. It is another object of the invention to provide pharmaceutical composition comprising Cilostazol Solid Dispersion Nanoparticles (SND) with Curcumin and Thymoquinone (TLS) tag.
3. It is another object of the invention to method for enhancing the therapeutic effectiveness of Cilostazol, comprising preparing Cilostazol Solid Dispersion Nanoparticles (SND) with Thymoquinone (TLS) and Curcumin tag using the emulsion solvent evaporation process.
4. It is another object of the invention to develop composition provides enhanced drug delivery and controlled release properties, allowing for synergistic effects of Thymoquinone and Curcumin in various therapeutic applications.
SUMMARY
The main microvascular consequence of diabetes mellitus (DM), diabetic nephropathy (DN), is what leads utmost to diabetic patients' greater risk of death. In the United States and most developed nations, diabetic nephropathy (30-50 %) is the main contributor to end-stage renal disease. Telmisartan (TLS) is a partial agonist of "peroxisome proliferator-activated receptor gamma (PPARc)" and an AT-1 receptor blocker also Curcumin (Cur) has been shown its antihyperglycemic properties, and both are water soluble and Cilostazol (CLT) is phosphodiesterase (PDE) inhibitor. It is also water-insoluble. Hence, Solid Nano dispersions were prepared as per the "Box-Behnken Design" using the emulsion solvent evaporation method to increase their bioavailability for both the drugs along with curcumin tagging individually. Formulations were then screened for solubility, percent CDR, particle size, and zeta potential. As the optimal formulation (having a desirability plot near 1), was evaluated
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for nephropathy in diabetic rats. Wistar rats were grouped and diabetes was inducted using Streptozotocin (single dose, 55 mg/kg, i.p) after 15 minutes of Nicotinamide (240 mg/kg) injection. Diabetic nephropathy usually appears 30 to 45 days after induction. With the screening of specific blood and urine indicators, the successful development of diabetic nephropathy was assessed. The kidneys and pancreas were used for the assessment of renal and pancreatic damage and histological evaluation, while biochemical and pharmacokinetic estimations were performed at certain time intervals on all rat groups. The results provide substantial evidence for the reno-protective and pancreas protective benefits of CLT and cur (SND-Solid Nano-dispersion) and TLS and Cur SND formulations by reducing levels of cytokines factor (IL-6), kidney, and lipid parameters. The combined inhibitory action of CLT along with Cur and TLS along with Cur may be the proposed mechanism.
BRIEF DESCRIPTION OF FIGURES
These and other features, aspects, and advantages of the present invention will become better understood when the following detailed description is read with reference to the accompanying figures in which like characters represent like parts throughout the figures, wherein:
Figure 1, illustrates a view of Schematic representation of the preparation of nanoparticulate drug delivery system for the present invention.
Fig. 2: illustrates a view of UV spectrum scanning of Cilostazol (a) and Curcumin (b) for the present invention.
Fig.3: illustrates a view of Simultaneous scanning of Curcumin and Cilostazol for the present invention.
Fig.4: illustrates a view of Desirability plot (a schematic diagram of the outcomes of optimization algorithms) for obtaining the best results (maximum solubility, maximum% CDR, minimal particle size, and acceptable zeta potential) for the present invention.
Fig: 5: illustrates a view of UV spectrum scanning of Telmisartan (a) and Curcumin (b) for the present invention.
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Fig: 6: illustrates a view of Simultaneous UV spectrum scanning of the combination of Curcumin and TLS for the present invention.
Further, skilled artisans will appreciate that elements in the figures are illustrated for simplicity and may not have been necessarily been drawn to scale. For example, the flowcharts illustrate the method in terms of the most prominent steps involved to help to improve understanding of aspects of the present invention. Furthermore, in terms of the construction of the device, one or more components of the device may have been represented in the figures by conventional symbols, and the figures may show only those specific details that are pertinent to understanding the embodiments of the present invention so as not to obscure the figures with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.
DETAILED DESCRIPTION:
For the purpose of promoting an understanding of the principles of the invention, reference will now be made to the embodiment illustrated in the figures and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, such alterations and further modifications in the illustrated system, and such further applications of the principles of the invention as illustrated therein being contemplated as would normally occur to one skilled in the art to which the invention relates.
It will be understood by those skilled in the art that the foregoing general description and the following detailed description are exemplary and explanatory of the invention and are not intended to be restrictive thereof.
Reference throughout this specification to “an aspect”, “another aspect” or similar language means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrase “in an embodiment”, “in another embodiment” and similar language throughout this specification may, but do not
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necessarily, all refer to the same embodiment.
The terms "comprises", "comprising", or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a process or method that comprises a list of steps does not include only those steps but may include other steps not expressly listed or inherent to such process or method. Similarly, one or more devices or systems or elements or structures or components proceeded by "comprises... a" does not, without more constraints, preclude the existence of other devices or other systems or other elements or other structures or other components or additional devices or additional systems or additional elements or additional structures or additional components.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The system, methods, and examples provided herein are illustrative only and not intended to be limiting.
The terms “a” and “an” herein do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items.
The terms “having”, “comprising”, “including”, and variations thereof signify the presence of a component.
Now the present invention will be described below in detail with reference to the following embodiment.
Example 1
Preparation of Solid Nano Dispersion of Curcumin tagged Cilostazol
SND was prepared using the emulsion solvent evaporation process. A weighed amount of CLT (100 mg) and weighed amount of Cur (100 mg), were mixed in 3 ml of methanol,
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and calculated amounts as per the design expert, polymer, and surfactant both were mixed with water (2mL). Add drop-by-drop organic (drug) solution to the aqueous phase during stirring. And then evaporated the rest in the Rota evaporator at 600 C under the required vacuum. A hot air oven was used as the secondary drying instrument, final product gets scrapped and stored in a desiccator.The approach used to create, refine, and characterize the Cilostazol Solid Dispersion Nanoparticles with Curcumin tag.
Finding the iso-absorptive point and choosing a suitable wavelength
Figure 2 illustrates the overlaid UV spectrum of the solutions of Cur and CLT (10 µg/ml each) in methanol and distilled water that was used to determine the iso-absorptive point (a wavelength of equal absorptivity of the two components).Cur and CLT's overlapping spectra were plotted between 200 and 800 nm. At 424 nm, curcumin displayed the highest absorbance, while CLT displayed the highest absorbance at 257 nm. The UV spectra of CLT and Cur in a methanolic buffer are displayed in Figures 2 (a) & (b) respectively and simultaneous spectra of CLT and Cur are shown in Figure 3. It showed that curcumin and cilostazol had no spectroscopic interaction. So, the individual peaks that can be used for the further analysis of both components that is 424 nm for Curcumin and 257 nm for Cilostazol.
Selection of optimized CLT-SDN
Using Design-Expert software, a desirability plot was utilized to find the ideal desirability for the composition of Curcumin-tagged CLT solid dispersion nanoparticles (version 12, Stat-Ease, Inc., MN, USA). Comparing the particle size for plain CLTSDN of optimized formulation withcurcumin-tagged According to CLT nanoparticles, drug encapsulation in curcumin matrix increased particle size and monodispersity of the particles. CLT nanoparticles without curcumin were produced with a particle size of 183.23 nm and polydispersity (PDI = 0.228). When curcumin was encapsulated, the nanoparticles grew to 219.67 nm (PDI = 0.258) but the size and the PDI were within permissible limits. The unbound curcumin molecule has a negative charge on its surface, and both curcumin and CLT are present. The zeta potential of the CLT solid dispersion nanoparticles was -27.3 mV without curcumin and -10.6 mV with curcumin tagging. When two drugs were encapsulated in nanoparticles, this was demonstrated by two distinct peaks at 424 nm (for curcumin) and 257 nm (for cilostazol) in the spectrophotometric study. All our nanoparticles had polymer coatings, allowing nanoparticle
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formulations to stabilize. PVP VA coating provides steric stability and consequently hinders nanoparticle aggregation.
CLT-15 (with Curcumin) has a slightly less % entrapment efficiency as compared to the without curcumin formulation i.e. CLT-15 (without cur). This may be due to the displacement of cilostazol molecules from the polymer matrix resulting in lesser entrapment efficiency. Without curcumin, the entrapment efficiency was little more than that with curcumin. There is no interference in the release of cilostazol from the encapsulating of the curcumin molecules in the same matrix, as seen by the nearly same drug release in both the dissolving media pH 1.2 and pH 6.8.
The particle size of the formulation CLT-15 (with Curcumin) was slightly more (219.67 nm) than the formulation CLT-15 (without Curcumin) (183.23 nm) but was still well below the standard nanoparticle size range. The enlarged particle size of the formulation CLT-15 (with Curcumin) may be due to the change in the chemistry of the polymer matrix of the nanoparticles due to the inclusion of the curcumin in the matrix. For the in vivo performance of the nanoparticles to escape detection and removal by the reticuloendothelial system, the zeta potential of the formulation CLT-15 (with Curcumin) was in the region of near neutral value (-10.6). (RES). The RES is made up of cells that descended from monocytes and can phagocytose foreign objects and particles. The liver houses 90% of the RES.
The polydispersity index (PDI) value of the formulation CLT-15 (with Curcumin) is less than 1 indicating good homogeneity of the product formulation. The more homogenous the nanoparticles are, as measured by the PDI, the smaller the value. The range of the PDI's numerical value is 0.0 (for a sample with absolutely uniform particle size) to 1.0. (for a highly polydisperse sample with multiple particle size populations). For polymer-based nanoparticle materials, values between 0.2 and 0.3 are most frequently regarded as acceptable in practice. Given the intricacy of the preparation procedure used, the practical yield of both formulations was within acceptable bounds.
Besides cilostazol, adding curcumin to the formulation adds more benefits for the treatment of diabetic nephropathy (DN). In the literature, curcumin has been shown to help in diabetic nephropathy. Curcumin, an effective antifibrotic medication whose potential therapeutic effects
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appear to be achieved through the lowering of NLRP3 inflammasome activity, is a well-known and prospective treatment for DN.So in combination with cilostazol, it’s a novel combination intended to make the DN treatment more effective with lesser side effects. The bioavailability of the nanoparticle formulation is always severalfold as compared to free drugs.
The ideal X1 and X2 values were 100 mg and 30 mg, respectively, as seen in Figure 3's desirability plot.The desirability plot shows the ideal value of solubility, % CDR, particle size, and zeta potential to obtain combined desirability of 1. Furthermore, the optimized Curcumin-tagged CLT solid dispersion nanoparticles' expected responses were contrasted with their actual values (Table 1). Solubility (Y1), % CDR (Y2), particle size (Y3), and zeta potential (Y4) of the improved formulation were examined as responses, and they were found to be 39.51 g/ml, 99.55%, 219.67 nm, and -10.6 mV, respectively. These values fell within the 95% confidence interval for the projected responses. Therefore, it implies that the optimization of CLT solid dispersion nanoparticles with a curcumin tag was accomplished.
Optimum conditions
Coded levels
Actual levels
PVP VA S 630 Concentration (mg)
-1.00
100.00
Poloxamer 407 concentration (mg)
-1.00
30.00
Response
Predicted Values
Experimental value
Solubility(µg/ml)
40.59
39.51
% CDR
100.66
99.55
Particle size (nm)
205.85
219.67
Zeta potential(mV)
-10.14
-10.6
Table 1: Optimal conditions, experimental results, and the projected response value under ideal conditions
Example 2
A nanosized amorphous solid dispersion was chosen among numerous solubility improvement techniques, and the formulation of SDN used the emulsion solvent evaporation technique. Cilostazol was chosen as the model drug and Curcumin was also added to the formulation, PVP VA S 630 and Poloxamer 407 were used as the carriers. So, to determine the content of Curcumin and Cilostazol, the simultaneous estimation method was used. A two-factor, three-
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level BBD was chosen to optimize the formulation batches for using the independent variables. The 3-D contour plots showed that the % CDR was maximum at the lesser concentration of Poloxamer 407, and the polymer that is PVP VA S 630 did not show any impact while for particle size, a lower concentration of Poloxamer 407 showed better effects, and PVP VA S 630 did not show any effect. So, the present solid dispersion formulation was stable at a higher concentration of PVP VA S 630 and a lesser concentration of Poloxamer. The desirability plot also indicated that optimized formulation at a lower region of polymer and surfactant concentration. Actual and predicted data from design expert also showed that there was a low prediction error for the fitted model. The partition coefficient was also calculated as 2.5, which indicated the lipophilic nature of the drug, and also the drug was found to have a low solubility that was 6 µg/ml, and the formulation was increased by 6.58 folds. In the FTIR studies, the pure drug has its intact peaks in combination with polymers which showed that there was no chemical combination. Overall DSC study also showed the amorphous nature of the formulation which further implies the better absorption and bioavailability of SDN. At 2 h, more than 90 % of the drug was released from the Nano Dispersion matrix which indicated a good solubility profile of CLT from the formulation. The zeta potential value (-10.6) of the CLT-15 formulation indicated good stability with a PDI value of 0.258. After 2h, the release slowly becomes constant until 99% of the drug was released. Consequently, the goal of the proposed investigation was achieved by the development of solid Nano Dispersion of CLT with an enhanced solubility profile. Also, the addition of curcumin to the formulation is a win-win take as it is reported to help in the treatment of DN.
Example 3
Preparation of SDN of TLS
SDN loaded with TLS (80 mg) and Cur (100 mg) were prepared using an emulsion solvent evaporation technique. In this process, the drug and Cur were dissolved in the organic phase (methanol), while the polymer (PVP VA S 630) and surfactant (Poloxamer 407) were dissolved in the water phase. The organic phase was gradually added drop by drop to the polymer phase under medium-speed stirring using a magnetic stirrer for approximately 30 minutes. After forming the emulsion, the solvent was evaporated under a vacuum using a Rota-evaporator. The resulting mixture was then placed in a hot air oven at 40°C for a day for secondary evaporation.
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Subsequently, the powdered nanoparticles were collected and stored in a desiccator for further analysis.
TLS and Cur were scanned simultaneously with a UV spectrophotometer
Figures 5 shows the UV spectrum scanning of TLS and Cur respectively and Figure 2illustrates the simultaneous UV spectrum scanning of Curcumin and Telmisartan mixturein a methanolic buffer, which showed that there was no spectral overlap between the two compounds.
TLS Solid Dispersion Nanoparticle Optimization and Characterization
The TLS-SDN was created utilizing a Box-Behnken design, which led to the creation of 17 formulations as well as assessing solubility, percent CDR, particle size, and zeta potential, and their results are shown in Table 2.
Indicating the prototype used for the batches is significant for solubility,% CDR, particle size, and zeta potential, the F-values of the optimized model for solubility,% CDR, particle size, and zeta potential of TLS-SDN were reported to be 1419.59 (p <0.0001), 39.92 (p <0.0001), 19.97 (p <0.0001), and 53.92 (p <0.0001), In addition, the lack of fit for all the responses for solubility, percent CDR, particle size, and zeta potential was 0.9179, 71.12, 0.9537, and 0.0721 respectively, indicating non-significance of the lack of fit, indicating that the model is significant.The R2 and adjusted R2 values also show the degree of variation between the proposed model and the research results. R2 and adjusted R2 for Y1 were 0.9985 and 0.9977, for Y2 they were 0.9478 and 0.9240, for Y3 they were 0.9008 and 0.8557, and for Y4 they were 0.9608 and 0.9430. The results show that the provided models accurately anticipated the outcomes. Additionally, all of the responses' R2 and modified R2 differences were less than 0.1, indicating that the proposed model fitted best.
Factor 1
Factor 2
Response 1
Response 2
Response 3
Response 4
Run
A: PVP VA S 630
B: Poloxamer 407
Solubility (±SD)
µg/ml
%CDR (±SD)
%
Particle size (±SD)
nm
Zeta (?) potential (±SD)
mV
1
400
65
3.876±0.02
89.66±0.12
444.72±2.4
-11.7±0.3
14
2
400
30
4.529±0.021
99.16±0.4
269.2±2.8
-11±0.3
3
400
100
2.546±0.01
81.75±0.32
320.3±1.5
-13.1±0.3
4
400
65
3.872±0.02
89.45±0.18
339.5±1.5
-11.3±0.4
5
700
65
4.012±0.016
88.2±0.04
455.6±4.2
-11.2±0.3
6
400
65
3.876±0.02
88.5±0.07
450.6±3.7
-11.7±0.4
7
100
65
3.92±0.002
91.32±0.07
478±3.5
-13.4±0.4
8
400
100
2.546±0.01
81.75±0.01
320.3±2.4
-13.1±0.3
9
400
65
3.75±0.021
89.55±0.004
444.8±2.3
-11.2±0.3
10
400
30
4.529±0.016
99.16±0.05
269.2±1.8
-11±0.3
11
700
65
4.012±0.004
88.2±0.014
455.6±3.4
-11.5±0.4
12
700
100
2.91±0.003
88.78±0.21
293.51±1.2
-13.2±0.4
13
700
30
4.435±0.002
97.67±0.15
336.8±0.5
-11.8±0.3
14
100
65
3.92±0.03
91.32±0.017
478±3.7
-13.4±0.3
15
100
30
4.801±0.006
99.68±0.14
303.5±1.5
-12.17±0.3
16
100
100
2.36±0.02
83.46±0.03
408.8±1.2
-14.99±0.3
17
400
65
3.876±0.001
89.66±0.16
449.68±1.6
-11.1±0.4
Table 2: SDN experimental design with independent variables and experimental response values
Example 4
Solid Dispersion Nanoparticles and self-micro emulsifying drug delivery systems (SMEDDS) are two different approaches for enhancing the solubility and bioavailability of poorly water-soluble drugs. Each approach has its advantages, and the choice between them
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depends on the specific characteristics of the drug and the desired formulation. Here are some advantages of solid nanodispersions over SMEDDS that are improved stability, ease of manufacturing, dose uniformity, lower risk of leakage and spillage, controlled release, and improved drug loading. The SDN formulation utilized the emulsion solvent evaporation technique, with Telmisartan as the model drug and Curcumin added to the mixture. The carriers employed were PVP VA S 630 and Poloxamer 407. To determine TLS and curcumin, the simultaneous UV calibration method was created. The solid dispersion in the nano range was made using the emulsion solvent evaporation process. The nanotechnological approach has garnered considerable attention as a strategy for improving drug solubility, presenting one of the most straightforward tasks in the realm of nanomedicines. Nanoparticles have been harnessed as effective platforms to enhance drug solubility. To quantitatively assess the primary impact and associated impact of the selected parameter on the response, a two-factor, three-level BBD was used. Maximum CDR and solubility were indicated by the 3D surface at lower Poloxamer 407 concentrations and PVP VA. The data show a decreased concentration of Poloxamer 407 showed a minimum particle size, PVP VA, on the other hand, has no effect. The SDN is stable at a lower concentration of polymer and surfactant. The desirability plot indicates optimized formulation at the lower polymer and surfactant concentration region. The distribution of the actual and anticipated data shows that the fitted model has a low prediction error. The partition coefficient (log P) was discovered to be 3.2, indicating that the medication is lipophilic. With a solubility of 0.09 µg/ml, TLS was found to have a poor solubility profile. The TLS+PVP+Poloxamer and TLS+Curcumin mix in the FTIR investigation both included all of the TLS peaks, proving that the drug's chemical integrity was not harmed. According to the overall DSC research, which showed the Nano Dispersion's amorphous nature, the TLS was successfully trapped in the Nano Dispersion matrix. At 2 hours, more than 90% of the drug was released from the Nano Dispersion matrix, indicating that the formulation's TLS had an excellent solubility profile. The TLS-15 formulation's zeta potential value (-12.17) and PDI value (0.311) suggested good stability. After two hours, the release starts to steadily increase until 99% of the medicine has been released. Thus, by creating an SDN of CLT with an improved solubility profile, the study's goal was realized.While solid dispersion nanoparticles offer several advantages, they also have some limitations and challenges that need to be considered
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during their development and application. Some of the limitations of solid dispersion nanoparticles include physical stability, limited drug compatibility, and manufacturing complexity. Despite these limitations, solid dispersion nanoparticles remain a promising approach for enhancing the solubility and bioavailability of poorly water-soluble drugs. Ongoing research and advancements in formulation technologies may help address some of these challenges and unlock the full potential of solid dispersion nanoparticles for drug delivery applications.
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We claim,
1. A method for preparing Cilostazol Solid Dispersion Nanoparticles (SND) with Thymoquinone (TLS) (80 mg) and Curcumin tag, comprising the steps of:
a) Mixing 100mg of Cilostazol (CLT) (100 mg), Thymoquinone (TLS) (80 mg) and 100mg of Curcumin (Cur) in 3 ml of methanol.
b) Preparing the aqueous phase by mixing predefined amounts of (PVP VA S 630) and surfactant (Poloxamer 407) with 2 mL of water
c) Adding the organic (drug) solution drop-by-drop to the aqueous phase during stirring.
d) Evaporating the remaining solvent in the Rota evaporator at 60°C under the required vacuum.
e) Performing secondary drying in a hot air oven.
f) Scraping and storing the final product in a desiccator.
2. The method as claimed in claim 1, wherein said process ensures the effective incorporation of Curcumin and Thymoquinone (TLS) with Cilostazol to form stable nanoparticles.
3. A pharmaceutical composition comprising Cilostazol Solid Dispersion Nanoparticles (SND) with Curcumin and Thymoquinone (TLS) tag, prepared by the method of claim 1.
4. The pharmaceutical composition as claimed in claim 3, exhibits improved drug delivery and enhanced therapeutic effects, owing to the synergistic action of Cilostazol, Thymoquinone (TLS) and Curcumin.
5. A method for enhancing the therapeutic effectiveness of Cilostazol, comprising preparing Cilostazol Solid Dispersion Nanoparticles (SND) with Thymoquinone (TLS) and Curcumin tag using the emulsion solvent evaporation process, as claimed in claim 1.
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Dated this 07/08/2023 G D Goenka University, Sohna Gurugram Road, Sohna, Haryana, India, 122103
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ABSTRACT
NANOPARTICULATE DRUG DELIVERY SYSTEM FOR THE MANAGEMENT OF DIABETIC NEPHROPATHY
The present invention relates to design, development, and evaluation of a nanoparticulate drug delivery system for the management of diabetic nephropathy. The solid lipid nanoparticles (SDN) loaded with Thymoquinone (TLS) (80 mg) and Curcumin (Cur) (100 mg) is prepared by dissolving Thymoquinone and Curcumin in the organic phase (methanol), dissolving the polymer (PVP VA S 630) and surfactant (Poloxamer 407) in the water phase, gradually adding the organic phase to the polymer phase under medium-speed stirring using a magnetic stirrer for approximately 30 minutes, resulting in the formation of an emulsion, evaporating the solvent under vacuum using a Rota-evaporator, placing the resulting mixture in a hot air oven at 40°C for a day for secondary evaporation and collecting the powdered nanoparticles. The composition provides enhanced drug delivery and controlled release properties, allowing for synergistic effects of Thymoquinone and Curcumin in various therapeutic applications. , Claims:We claim,
1. A method for preparing Cilostazol Solid Dispersion Nanoparticles (SND) with Thymoquinone (TLS) (80 mg) and Curcumin tag, comprising the steps of:
a) Mixing 100mg of Cilostazol (CLT) (100 mg), Thymoquinone (TLS) (80 mg) and 100mg of Curcumin (Cur) in 3 ml of methanol.
b) Preparing the aqueous phase by mixing predefined amounts of (PVP VA S 630) and surfactant (Poloxamer 407) with 2 mL of water
c) Adding the organic (drug) solution drop-by-drop to the aqueous phase during stirring.
d) Evaporating the remaining solvent in the Rota evaporator at 60°C under the required vacuum.
e) Performing secondary drying in a hot air oven.
f) Scraping and storing the final product in a desiccator.
2. The method as claimed in claim 1, wherein said process ensures the effective incorporation of Curcumin and Thymoquinone (TLS) with Cilostazol to form stable nanoparticles.
3. A pharmaceutical composition comprising Cilostazol Solid Dispersion Nanoparticles (SND) with Curcumin and Thymoquinone (TLS) tag, prepared by the method of claim 1.
4. The pharmaceutical composition as claimed in claim 3, exhibits improved drug delivery and enhanced therapeutic effects, owing to the synergistic action of Cilostazol, Thymoquinone (TLS) and Curcumin.
5. A method for enhancing the therapeutic effectiveness of Cilostazol, comprising preparing Cilostazol Solid Dispersion Nanoparticles (SND) with Thymoquinone (TLS) and Curcumin tag using the emulsion solvent evaporation process, as claimed in claim 1.