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Formulation, design and optimization of antidiabetic drug loaded microspheres

• Original Paper
• Published: 07 July 2022
• Volume 80 , pages 6171–6196, ( 2023 )

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• Tabasum Siraj Mulla 1 ,
• Vijay Rajaram Salunkhe 1 ,
• Somnath Devidas Bhinge   ORCID: orcid.org/0000-0002-5959-5833 3 &
• Nitin Mohire 2  

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The present research aim is to develop the tablet formulation containing microspheres and encapsulating microsphere with antidiabetic drug specially Sitagliptin Phosphate Monohydrate and poly lactic co glycolic acid (PLGA) as a polymer. Preformulation study of the selected drug was carried out. Then, the microspheres were prepared by factorial design, i.e., Design-Expert 12 software (Stat-Ease Inc., USA) was used for designing of experiment, to study interaction between independent variables and dependent variables and deriving optimum formulation. Spray dryer was used for preparation of microspheres. The zeta potential, particle size, infrared spectral analysis, scanning electron microscopy, % drug content, encapsulation efficiency and % drug release were evaluated. Optimized batch F3 showed an average particle size 2500.6 nm. The in vitro drug release at 12th hour and % drug entrapment efficiency of optimized batch F3 was found to be 92.35% and the 34.00%, respectively. The final product has lowered particle size 2500.6 nm and it is focused for well acceptable and suitable due to significant drug release. The final tablet was prepared from optimized batch F3. The precompression parameters, i.e., flow properties of granules, were carried out, and then, post-compression parameters like weight variation, thickness, hardness, friability, % drug content and % drug release were evaluated. The stability study and in vitro antidiabetic study was carried out for tablet. The final product is well acceptable, suitable, palatable, easy for administration and elegant.

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Acknowledgements

We express our sincere thanks to Dr. C. S. Magdum, Principal, Rajarambapu College of Pharmacy, Kasegaon, MS—415404, INDIA.

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Mulla, T.S., Salunkhe, V.R., Bhinge, S.D. et al. Formulation, design and optimization of antidiabetic drug loaded microspheres. Polym. Bull. 80 , 6171–6196 (2023). https://doi.org/10.1007/s00289-022-04325-9

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Received : 07 October 2021

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DOI : https://doi.org/10.1007/s00289-022-04325-9

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A bio-ionic liquid based self-healable and adhesive ionic hydrogel for the on-demand transdermal delivery of a chemotherapeutic drug †.

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a Ionic Liquids Research Laboratory, Department of Chemistry, Sardar Vallabhbhai National Institute of Technology, Surat 395007, Gujarat, India E-mail: [email protected]

b ISIS Pulsed Neutron & Muon Source, STFC Rutherford Appleton Laboratory, Harwell Campus, Didcot, UK

c Technology and Innovation Centre, Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1RD, UK

The non-invasive nature and potential for sustained release make transdermal drug administration an appealing treatment option for cancer therapy. However, the strong barrier of the stratum corneum (SC) poses a challenge for the penetration of hydrophilic chemotherapy drugs such as 5-fluorouracil (5-FU). Due to its biocompatibility and capacity to increase drug solubility and permeability, especially when paired with chemical enhancers, such as oleic acid (OA), which is used in this work, choline glycinate ([Cho][Gly]) has emerged as a potential substance for transdermal drug delivery. In this work, we examined the possibility of transdermal delivery of 5-FU for the treatment of breast cancer using an ionic hydrogel formulation consisting of [Cho][Gly] with OA. Small angle neutron scattering, rheological analysis, field emission scanning electron microscopy, and dynamic light scattering analysis were used to characterize the ionic hydrogel. The non-covalent interactions present between [Cho][Gly] and OA were investigated by computational simulations and FTIR spectroscopy methods. When subjected to in vitro drug permeation using goat skin in a Franz diffusion cell, the hydrogel demonstrated sustained release of 5-FU and effective permeability in the order: [Cho][Gly]–OA gel > [Cho][Gly] > PBS (control). The hydrogel also demonstrated 92% cell viability after 48 hours for the human keratinocyte cell line (HaCaT cells) as well as the normal human cell line L-132. The breast cancer cell line MCF-7 and the cervical cancer cell line HeLa were used to study in vitro cytotoxicity that was considerably affected by the 5-FU-loaded hydrogel. These results indicate the potential of the hydrogel as a transdermal drug delivery vehicle for the treatment of breast cancer.

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A bio-ionic liquid based self-healable and adhesive ionic hydrogel for the on-demand transdermal delivery of a chemotherapeutic drug

R. Pansuriya, J. Doutch, B. Parmar, S. K. Kailasa, N. Mahmoudi, C. Hoskins and N. I. Malek, J. Mater. Chem. B , 2024, Advance Article , DOI: 10.1039/D4TB00510D

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Formulation and evaluation of gastro-retentive floating bilayer tablet for the treatment of hypertension

Balaji maddiboyina.

a Department of Pharmacy, Vishwabharathi College of Pharmaceutical Sciences, Guntur, Andhra Pradesh, 522009, India

Mudavath Hanumanaik

Ramya krishna nakkala, vikas jhawat.

b Department of Pharmacy, School of Medical & Allied Sciences, GD Goenka University, Gurgaon, 122103, India

Pinki Rawat

c Maharana Pratap College of Pharmacy, Kanpur, 209217, Uttar Pradesh, India

d Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, 16278, Saudi Arabia

Ahmed I. Foudah

Majed m. alrobaian.

e Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Taif University, Taif, 21974, Saudi Arabia

Rahul Shukla

f Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow, 226002, Uttar Pradesh, India

g School of Pharmacy, Sharda University, Greater Noida, Uttar Pradesh, India

Prashant Kesharwani

h Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India

The paper aimed to progress an ideal gastro retentive drug delivery system intended for directing Losartan and Hydrochlorothiazide as a fixed-dose combination for anti-hypertensive therapy. The bilayer tablets were primed through direct compression method. Losartan was formulated by means of a floating layer expending hydrophilic swellable polymer Hydroxy Propyl Methyl Cellulose K4M, ethyl cellulose (4cps) as a buoyancy enhancer, sodium bicarbonate as a gas spawning agent. The amount of polymer blends remains optimized using 2 3 full factorial designs. The clout of experimental factors such as swelling agent concentration, buoyancy enhancer and gas generating agent on floating lag time, total floating time, T50% and % drug release remain investigated to get optimized formulation. The responses remain analyzed using Analysis of variance, and polynomial equation stood created for every retort using Multiple linear regression analysis. Entirely preparations floated for more than 12 h. The release pattern of losartan stood fitted to diverse models based on the coefficient of correlation (r). All the formulations, except F2, showed the Korsemeyer-Peppas model as the best fit model. Formulation F2 showed the zero-order model. Diffusion exponents (n) remained indomitable designed for entirely formulations (0.45–0.89), accordingly the chief drug discharge mechanism was non-fickian (anamolous) transport. Formulation F4 containing 20% w/w Hydroxy Propyl Methyl Cellulose K4M, 15% Sodium bicarbonate and 5% ethyl cellulose (4cps) was the best formulation as per the range of drug release remain institute to be more than 95 % in 12h and floating lag time was 20.15 s. The immediate-release layer stood optimized using crospovidone and Indion 414 as a super disintegrant. Formulation A8 containing 2% Indion 414 was considered as optimized formulation as it released 99% drug within 35 min and possessed less disintegration time. Optimized formulation F4 from the controlled-release layer and A8 from immediate-release layer was used to formulate bilayer tablet. The optimized formulation was imperilled to stability reading for three months at 40 ○ C/75% relative humidity. The stability revision exhibited no substantial alteration in the appearance of tablets, floating characteristics, drug content and in-vitro drug dissolution. Consequently, a biphasic drug release design was effectively accomplished over the formulation of floating bilayer tablets.

Bi-layer floating tablets; Optimization; Superdisintegrants; Release-retarding polymers; Drug delivery; Pharmaceutical science; Biomedical engineering; Health sciences; Public health; Cardiology; Clinical research.

1. Introduction

The controlled release drug delivery systems (CDDS) owning the capacity to be engaged in the stomach remain entitled as Gastro Retentive Drug Delivery Systems (GRDDSs), then both retain aid in enhancing the oral precise release of medications through unremittingly discharging drug afore absorption window designed for an extended period. Further being capable to persistently and sustainably release medication towards the small intestinal absorption window, the enhancements delivered since GRDDSs embrace: attaining a further substantial then extended therapeutic outcome and consequently falling the incidence of management epochs, only if further effective management of resident stomach ailments, and curtailing equally lower-tract deactivation of the medication and impacts on the lower intestinal flora. Subsequently that, innumerable methodologies of this sort as floating, bioadhesive, swelling and escalating systems obligate remain advanced toward surge the gastric retaining period of a dosage form [ 1 ].

Bilayer tablet remains a novel epoch designed for the effective advance of controlled delivery design laterally through numerous sorts to deliver an approach of efficacious drug transport system [ 2 , 3 ]. Bi-layer tablet remain seemly intended for ensuing discharge of two medications in combination, discrete two discordant constituents then similarly designed for sustained discharge tablet in that single layer is immediate release as initial dose and the subsequent layer is the maintenance dose. Bilayer tablet remains enhanced favourable knowledge to overwhelmed the inadequacy of the single-layered tablet [ 4 , 5 ].

Hypertension (HTN) otherwise similarly notorious as high blood pressure (BP), occasionally arterial hypertension, remains a chronic medicinal situation and that the BP in the arteries is upraised. This entails the heart to effort durable than regular to circulate blood over the blood vessels. The BP implicates two extents, systolic and diastolic, that are reliant on either the heart muscle remains constricting (systole) or relaxed (diastole) amid beats. Normal BP is at or beneath 120/80 mmHg. High BP is supposed to remain extant if it is obstinately at or beyond 140/90 mmHg [ 6 , 7 ].

Losartan potassium (LSP) is a persuasive, vastly precise angiotensin II type 1 (AT1) receptor antagonist through anti-hypertensive action. It remains eagerly absorbed after the gastrointestinal tract through oral bioavailability of around 33% and a plasma elimination half-life extending after 1.5–2.5 h. Subsequent oral management, losartan is hastily absorbed, and formerly roughly 14% of a losartan dose remains metabolized into active carboxylic acid metabolite (E3174) by CYP2C9. E3174 is 10–40 fold further persuasive than owned parent composite, then the probable half-life sorts after 6–9h. Hydrochlorothiazide (HCT) is a thiazide diuretic and is adopted in the supervision of slight to modest hypertension. It remains precise marginally soluble in water holding a plasma half-life of 6h–14h and protein binding 67.9%. It remains variably absorbed from the gastrointestinal tract, eliminated rapidly by the kidney and primarily excreted in unchanged form in urine [ 8 ].

A fixed-dose combination of losartan potassium (LSP)/Hydrochlorothiazide (HCT) remedy might remain a consistent prime for anti-hypertensive management, comprising meant for preliminary remedy in patients with BP elevation >20/10 mmHg beyond management target. Particular adverse effects concomitant with HCT, comprising improved peril designed for new-onset diabetes mellitus, might be equipoise by losartan [ 8 ]. Losartan remained recurrently managed through HCT in the Losartan Intervention for Endpoint reduction in hypertension (LIFE) revision, in which there stood a 25% peril decline for stroke in the losartan-based paralleled through the atenolol-based supervision group. The efficiency, permissibility, and suitability of Losartan/HCT combination treatment might surge patient amenability and lessen peril for stroke, an unfortunate consequence in patients with hypertension [ 9 ].

The combinations of Losartan potassium and Hydrochlorothiazide obligate remain revealed to have an improver outcome on BP decline, reducing BP to a greater mark than either constituent alone. Several pharmacological interactions support the potential further anti-hypertensive benefits from combined therapy with the angiotensin-II receptor (type AT1) antagonist and diuretics. The combined drug is adopted as a fixed-dose permutation to diminish the quantity of medicines [ 10 ].

An experimental design stays a statistical strategy, which suggests or instructs a customary of permutation of variables. The numeral and outline of certain design facts inside the pilot section hinge on the quantity of issues such need to be probable. Provisional on the sum of aspects, their intensities, probable interfaces and directive of the exemplary, several experimental designs remain preferred. The most straightforward factorial design remains the two factorial design, in which two aspects are deliberated apiece at two levels, hints to four experiments that remain found in 2-dimensional factor space at the corners of a rectangle. The number of experiments is assumed by 2 n , where ‘n’ is the number of factors [ 11 ].

2. Materials and methods

LSP, HCT, HPMC K4M was obtained from SARC Research labs, Hyderabad. CrosPovidone, Indion 414 was procured from HIQ Labs, Hyderabad.

2.1. Compatibility studies of drug and polymers

2.1.1. fourier transform infrared spectrometry (ftir).

Approximately 300mg of KBr was weighed and grind to a fine powder, and then approximately 1mg of the Pure drug/combination of drug-excipients was added and grinded well to mix the sample with the KBr and then press this KBr mixer and made a palate by using IR press at the pressure of 8-tons [ 12 ].

2.1.2. Differential Scanning Calorimetry (DSC)

The DSC exploration confirmed physical stature of inherent medication esoteric the nanoparticles. The sample remains placed and wrapped typical aluminium pan and was perused between 25 °C to 300 °C with a heating rate of 10°C/minute beneath nitrogen atmosphere. A blank aluminium pan served as reference [ 13 ].

2.2. Preparation and optimization of bilayer floating tablets

2.2.1. formulation of immediate-release tablets of hct.

The medication along with super disintegrants crospovidone/Indion 414, microcrystalline cellulose and lake sunset yellow were weighed and passed through sieve no 60 discretely as displayed in Table 1 . The concentration of crospovidone and Indion 414 were 2, 3, 4, 5 % and 0.5, 1, 1.5, 2 % respectively. The admixture of powders remains swayed out by utilizing a pestle and mortar intended for 10 min. Finally, the prepared powder blend lubricated through magnesium stearate and colloidal silicon dioxide then further assorted in mortar pestle for 3 min. The prepared powder blend was manually fed into the 4 mm flat-faced punches and the tablets having a final weight of 50 mg remained primed by direct compression (DC) on ten stations rotary tablet machine (Rimek Mini Press-I) [ 14 ].

Table 1

Formulation Design of immediate-release tablets of HCT.

2.2.2. Preliminary trial batches (PTB) of controlled release floating tablet of losartan

The PTB remain primed by expending hydrophilic polymers HPMC K4M, effervescent agent (sodium bicarbonate) and buoyancy enhancer (ethylcellulose 4 cps) at different concentrations and % CDR, FLT and total floating duration remain patterned and on such premise stages of beyond constituents remain fixed as follows: HPMC K4M: 20 %–30 % w/w, Sodium bicarbonate: 10 % to 15% w/w and Ethylcellulose (4 cps): 5 % to 10 w/w.

2.3. Optimization of LSP using 2 3 full factorial designs

By means of 3 factors at 2 levels, full-factorial trials entailing of 8 preparations, remain intended. (2 3 = 8) with one extra checkpoint formulation, as shown in Table 2 [ 15 ].

Table 2

Factorial Design Batches of LSP floating tablet.

Where X 1 = Conc. of HPMC K4M (%), X 2 = Conc. of NaHCO 3 (%) and X 3 = Conc. of Ethyl cellulose (%).

Coded and actual values of X 1 : -1 = 20, +1 = 30, 0 = 25.

Coded and actual values of X 2 : -1 = 10, +1 = 15, 0 = 12.5.

Coded and actual values of X 3 : -1 = 5, +1 = 10, 0 = 7.5.

2.3.1. Formulation of controlled release floating tablets of LSP

Tablets enclosing 50 mg of LSP was primed, conferring to the intention portrayed in Table 3 , by DC. The corresponding powders, explicitly Losartan potassium, release-retarding polymer HPMC K4M, buoyancy enhancer ethyl cellulose (4cps) and gas generating agent NaHCO 3 remain conceded over sieve no. 60, distinctly as exhibited in Table 3 . Mingling of powders remain conceded out expending a pestle and mortar meant for 10 min. Colloidal silicon dioxide and magnesium stearate remained, formerly auxiliary to the assorted powders. Admixture stood sustained intended for another 3 min. Lastly, 300 mg of respective mixture remain weighed and served physically into the die of a 10 station rotary tablet contrivance, fortified through flat-faced punches (9.5 mm), to result the preferred tablets [ 16 ].

Table 3

Composition for the controlled release floating tablets of Losartan potassium.

2.4. Formulation of bilayer floating tablets

Optimized formulation from the immediate-release layer and controlled release layer was used to formulate bi-layer floating tablet of LSP and HCT. Accurately weighed 50 mg of immediate-release stratum powder blend then 300 mg of controlled-release floating layer powder blend separately. Lots of bilayer tablets remain primed by direct compression practice accordingly. Initially controlled release powder composite served physically into the dies of 10 stations rotary tablet contrivance and formerly compacted at low compression force to the designed uniform layer of powder. Consequently, immediate-release layer's powder blend of HCT was added over pre-compressed immediate-release layer then improved compression force and then compressed by tablet punching contrivance through by means of 9.5 mm flat-faced punch [ 17 ].

2.5. Characterization parameters

Appearance: The appearance was acknowledged visually through proving the colour variance.

Hardness: It was measured using Monsanto hardness tester.

Thickness: A Mitutoyo Digital Vernier calliper stood adopted to regulate the thickness of ten arbitrarily designated tablets [ 18 ].

Friability: 10 tablets remained arbitrarily designated and employed in the drum of tablet friability check equipment then stood familiar to revolve 100 intervals in 4 min. The tablets remained impassive then precisely balanced. The % weight loss stood ascertained [ 19 ].

where, % F = Friability in %, W = Initial wt of tablets, Wt = Wt of tablets after revolution.

Weight variation: 20 tablets remain randomly designated, the average weight stood ascertained, and then they remain weighed individually to calculate the standard deviation.

Drug content: 20 tablets remain balanced and crumpled. An extent of powder corresponding to the quantity of single tablet (50 mg) stood accurately weighed and reassigned to 100ml volumetric flask. Volume was prepared up to the streak through methanol in a 100ml volumetric flask then Sonicated intended for 10–15 min. The drug content remain indomitable by UV spectroscopy at a wavelength of 270nm for HCT; 234nm for Losartan potassium [ 20 ].

2.5.1. Tablet floating behaviour

Cconcisely, tablets remain allocated in a glass beaker, carrying 200 mL of 0.1 N HCl, asserted in a water bath at 37 ± 0.5 °C. The floating lag time remains notorious as the time inside tablet prologue and its buoyancy. The entire floating extent the time through that tablet remnant buoyancy remains reported.

2.5.2. Swelling index

The water uptake revision of the tablet stood prepared expending USP dissolution apparatus II. The vehicle adopted remains distilled water, 900 ml revolved at 50 rpm. The vehicle stay retained at 37 ± 0.5 °C through the revision [ 21 ]. Subsequently a designated period interval, the tablets remained introvert, marked to take away surplus water then balanced. Swelling individualities of the tablets remain uttered in rapports of water uptake (WU) as:

2.5.3. In vitro disintegration test for immediate release HCT tablets

Arbitrarily 6 tablets stood designated from the respective lot for disintegration test. Disintegration test remain accomplished deprived of the disc in simulated gastric fluid (37 + 0.5 0 c) expending disintegration apparatus.

2.6. In vitro dissolution studies [ 22 ]

2.6.1. immediate release hct tablets.

It stood conceded out on type II apparatus exhausting the paddle. 500 ml of pH 1.2 buffer (0.1N HCl) as dissolution medium at 37 ± 0.5 °C through the rotational speediness of 50 rpm. The illustrations remain introvert at a determined time interim up to 40 min and analyzed on UV spectrophotometer at 270 nm.

2.6.2. Controlled-release floating tablets of losartan potassium

It remains conceded out on type II apparatus expending the paddle. 900 ml of pH 1.2 buffer (0.1N HCl) as dissolution medium at 37 ± 0.5 °C through a rotational speediness of 50 rpm. The sample stood introvert at scheduled period interval adequate 12h and explored on UV spectrophotometer at 234 nm.

2.6.3. Floating bi-layer tablet of losartan and HCT

Dissolution of the bilayer tablets remain conceded out on type II apparatus using a paddle. 900 ml of pH 1.2 buffer (0.1N HCl) as dissolution medium at 37 ± 0.50C with a rotational speediness of 50 rpm. The sample stood introvert at scheduled period interval up to 12h and evaluated on UV spectrophotometer by simultaneous estimation method [ 23 ].

2.7. Statistical analysis of responses

The Surface response plot, Contour plots were drawn using Design Expert Software v 8.0.6.1 (STATEASE).

2.8. Release kinetics

In edict to apprehend the contrivance and kinetics of drug discharge, the outcomes of the in vitro drug discharge revision stood fitted through innumerable kinetic reckonings namely zero-order (% release vs time), first-order (log% unreleased vs time), and Higuchi matrix (% release vs square root of time). To delineate a exemplary that resolve epitomize a restored fit designed for the preparation, drug release statistics advance considered by Peppas equation, Mt/M∞ = ktn, where Mt is the quantity of drug released at time t and M∞ is the quantity released at the time ∞, the Mt/M∞ is the fraction of drug released at time t, k is the kinetic constant and n is the diffusion exponent, a degree of the principal contrivance of drug discharge. Regression coefficient (r 2 ) values remain contrived for the linear curves acquired by regression exploration of the beyond plots [ 24 ].

2.9. Stability studies

Stability application of the enhanced preparation remains conceded out as conferring to the ICH recommendations, at 40 ± 2 °C/75 ± 5% RH by adopting Thermolab TH 90S stability chamber for 3 months. The carried remain observed for drug content, floating behaviour and in vitro drug release profile [ 25 ].

3. Results & discussion

3.1. compatibility studies of drug and polymers, 3.1.1. fourier transform infrared spectrometry (ftir).

It was found that there was no possible interaction in between drug and super disintegrants in their original form and mixture form as displayed in Figure 1 .

FTIR spectrum of (a) pure LSP (b) pure HCT (c) HCT + Crospovidone + MCC + Magnesium stearate + Colloidal silicon dioxide + Lake sunset yellow (D) HCT + Indion 414 + MCC + Magnesium stearate + Colloidal silicon dioxide + Lake sunset yellow (E)Losartan Potassium + HPMC K4M + Ethyl cellulose + Sodium bicarbonate + MCC + Magnesium stearate + Colloidal silicon dioxide (F) LSP + HCT + HPMC K4M + Ethyl cellulose + Sod bicarbonate + Indion 414 + MCC + Magnesium stearate + Colloidal silicon dioxide + Lake sunset yellow.

3.1.2. Differential Scanning Calorimetry (DSC)

Compatibility examinations stood similarly conceded by using DSC, which is a qualitative analytical tool for assessing the interactions. The thermograms indicated no significant change in drug endotherm peaks in mixture samples, as shown in Figure 2 .

Differential Scanning Calorimetry (DSC) spectrum of (a) Pure LSP (b) pure HCT (C)HCT + Crosspovidone + MCC + Magnesium stearate + Colloidal silicon dioxide (D) HCT + Indion 414 + MCC + Magnesium stearate + Colloidal silicon dioxide (E) LSP + HPMC K4M + Ethyl cellulose + Sodium bicarbonate + MCC + Magnesium stearate + Colloidal silicon dioxide (F) LSP + HCT + HPMC K4M + Ethyl cellulose + Sodium bicarbonate + MCC + Indion 414 + Magnesium stearate + Colloidal silicon dioxide + Lake sunset yellow.

3.2. Preparation and optimization of bilayer floating tablets

The contemporary concerns was carried out to advance a bilayer floating drug release practice of LSP and HCT to augment absorption and bioavailability through amassed the gastric retention period of the drug. In apprehension towards this method, the crucial requisite remains to float the tablet in a gastric environs and further proceedings for the development of floating bilayer tablets.

Preformulation study remain toted out expending different concentration level of HPMC K4M, Sodium bicarbonate and Ethylcellulose (4cps) for floating layer and Crospovidone and Indion 414 for immediate release layer to optimize the formulations. The criteria for selection of optimum immediate-release tablet were in vitro disintegration period and in vitro drug delivery. Eight formulations remain prepared using different concentration of Crospovidone (A1-A4) and Indion-414 (A5-A8). Formulation A8 containing 2% of Indion 414 was optimized formulation.

3.3. Optimization of LSP using 2 3 full factorial design

A full factorial 2 3 = 8 experiments were designed with one extra checkpoint formulation. Optimization of the HBS system was made based on 3 dependent variables viz: i) Drug release at 12h ii) time required to 50% of drug discharge iii) Floating lag time. The preparations were studied for the effect of concentration of swelling agent (HPMC K4M), the concentration of gas spawning agent (Sodium bicarbonate) and buoyancy enhancer (ethylcellulose 4cps) on the dependent variables (response). To know the effect of each variable on the responses, the variables and responses were selected for the Analysis of Variance (ANOVA) and multiple linear regression analysis. Formulation F4 containing 20% of HPMC K4M, 15% sodium bicarbonate and 5% of ethyl cellulose was optimized formulation.

3.4. Formulation of bilayer floating tablets

Optimized formulation A8 from the immediate-release layer and F4 from the floating layer was used for the formulation of the bilayer tablet. Direct compression method employed for all formulations was found to be satisfactory for instance the physicochemical evaluation constraints remained inside the permissible limits.

3.5. Characterization parameters

3.5.1. characterization parameters for immediate release tablets of hct.

The thickness of the prepared tablet is in the range of 2.523 ± 0.036 to 2.736 ± 0.019mm. The hardness of the formulated tablets remain institute in the array of 3.4–3.8 kg/cm 2 . The friability of all the tablets remain institute to be less than 1%, i.e. in the array of 0.231%–0.426% as displayed in Table 4 . The formulation A8 shows lowest disintegration time 11.27 s because of its swelling tendency on wetting.

Table 4

Evaluation parameters for immediate release tablets of HCT.

3.5.2. Characterization parameters for floating tablets of LSP

The thickness of the prepared tablet remains in the range of 3.908 + 0.046 to 3.988 + 0.051mm. The hardness of the formulated GRDDS of Losartan remains institute in the array of 5.2–5.6 kg/cm 2 . The friability of entire tablets remain institute to be less than 1%, i.e. in the array of 0.205%–0.419% as displayed in Table 5 .

Table 5

Evaluation parameters for floating tablets of Losartan Potassium.

3.5.2.1. Tablet floating behaviour

The exploration discloses that entire preparations retain good floating effects. The order of floating lag period remains institute to be: F3<F4<F7<F1<F5<C1<F8<F2<F6.

3.5.2.2. Swelling index

The swelling index remains extending in amid 50.59 %–79.13 % as displayed in Table 6 . High level of HPMC K4M exhibited maximum water uptake, indicated the extreme swelling property. The concentration of NaHCO 3 improved commencing 10%–15% swelling index remain amplified owing to an upsurge in degree of pore development then subsequently, swift hydration of the tablet milieus.

Table 6

Results of the floating property of the losartan floating tablets.

3.6. In vitro dissolution studies

The dissolution contour of the preparations containing both the disintegrants was compared. Therefore, formulation A8 having disintegrant Indion 414 in the concentration of 2% remain designated as per the optimized formulation by way of it disintegrates very swiftly in 11.27 s and releases more than 99% drug in 35 min as exhibited in Table 7 and Figure 3 A. Thus batch A8 of an immediate-release layer and batch F4 of the floating layer was used to formulate bilayer floating tablets of LSP and HCT.

Table 7

In vitro drug release study for HCT immediate-release tablets.

In vitro drug release study for A) HCT tablets B) Losartan floating tablets.

Formulae F4 containing the highest gas-forming agent concentrations and lowest HPMC K4M concentration showed the highest drug release, as shown in Table 8 and Figure 3 B. These release revisions exposed that the imperative of release remained institute to exist F4>F3>F1>C1>F7>F8>F5>F6>F2.

Table 8

In-vitro drug release study for Losartan floating tablets.

3.7. Statistical analysis of responses

Multiple linear regression analysis was performed for dependent variables Q12, FLT and T50% as shown in Figure 4 . The most significant coefficient means the causal factor has a more potent influence on the response. The values of the correlation coefficient for Q12, FLT and T50% are 0.9996, 0.9995 and 0.9189, respectively. The above concentration of ingredients was almost the same as the value of factorial batch F4 formulation. Consequently, batch F4 remained desirable by means of the optimized batch, as shown in Figure 5 .

3D Response Surface plot showing the effect of factorial variables on: A, B-% CDR at 12h; C, D- Floating lag time; E, F- T 50%.

Numerical optimization Solution Tool Ramps.

A checkpoint lot remains primed at X1 = 0 level, X2 = 0 level and X3 = 0 level as displayed in Table 9 , indicates the results of checkpoint batch. From the equation generated from regression analysis by putting the values of X1, X2 and X3 in percentage it remains probable such the significance of Q12 of the checkpoint batch ought to be 79.88 %, the value of FLT of the checkpoint batch ought to be 39.66 s and T 50% of checkpoint batch ought be 6.629h. The outcomes achieved with checkpoint batch are precise adjacent to expected values. Consequently, we can accomplish which the statistical exemplary remains mathematically expedient.

Table 9

Dissolution Parameters for 2 3 Full Factorial Design formulations.

3.8. For floating bilayer tablets

Composition of bilayer floating tablet includes an immediate-release layer (A8 Batch) and controlled release floating layer (F4 Batch) as exhibited in Table 10 . The average weight, thickness and hardness of primed tablet remain institute to exist 348mg, 4.62 mm and 5.4 kg/cm 2 correspondingly. The drug content of the primed bilayer tablets remain establish to be 98.23 (LSP) and 99.48 (HCT). The In vitro drug release of the primed bilayer tablets remains institute to stay 97.32% (LSP for 12h) and 98.56% (HCT in 35 min).

Table 10

Comparison of the observed value and predicted value for checkpoint formulation C1 and optimized formulation F4.

3.9. Release kinetics

The results ascertained such the release mechanism for LSP floating tablets remained by diffusion and swelling controlled mechanism, i.e. Non-fickian/anomalous transport where n value lies amid 0.45 to 0.89 for entire preparations as displayed in Table 11 . From the ‘n’ value of optimized formulation (0.560) acquired it can remain assumed that the diffusion charted Non-fickian mechanism and from regression coefficient value (0.9851) it can be said that it follows Peppas model for drug release.

Table 11

Kinetic data of various models for release study.

3.10. Stability studies

Stability study was performed for optimized floating bilayer tablet formulation at 40 ± 10C and RH 75% for 3 months. The illustrations remain examined for hardness, percent drug content, floating behaviour and in-vitro drug release revisions. The results are given in Table 12 . No substantial variance was perceived for the beyond parameters.

Table 12

Results for stability studies of optimized formulation.

4. Discussion

An effort remained thru to upsurge the oral bioavailability of Losartan and Hydrochlorothiazide fixed-dose combination through retentive the dosage form in the stomach intended for a more extended epoch. This remains accomplished by evolving a gastroretentive floating drug delivery system. The precise tablets remain primed to surge the bioavailability of the medications by employing the medications to a complete degree evading avoidable incidence of dosing and consequently the first-pass metabolism.

Losartan and Hydrochlorothiazide combination indicated for hypertension with left ventricular hypertrophy adults. Losartan was having a plasma elimination half-life extending after 1.5–2.5h with oral bioavailability of about 33% needs gastro-retention to improve bioavailability and to evade the first-pass consequence, on the other hand, Hydrochlorothiazide having a half-life of 8 h–14 h with 67.9 % protein binding needs immediate release. To achieve patient compliance by controlling blood pressure for an extended duration of time, a floating bilayer tablet of this fixed-dose combination was suggested.

For the formulation of bilayer floating tablets floating as well as immediate release layers were optimized separately. Crospovidone and Indion 414 were used as super disintegrants. HPMC K4M stood practiced as matrix creating gelling agent. Ethylcellulose adopted as a buoyancy enhancer and release retardant. Other excipients used were MCC (Diluent), NaHCO 3 (gas generating agent), Magnesium stearate (lubricant) and colloidal silicon dioxide (glidant).

FTIR and DSC thermograms inveterate the nonappearance of any drug/polymers/excipients interfaces. A physical mixture of medication and polymer were considered by FTIR spectral exploration designed for every physical along with chemical disparity of the medication. From the outcomes, it remain determined that there existed no interfering in the functional groups as the principal peaks of the Losartan and Hydrochlorothiazide remain institute to be intact, designating they stood compatible chemically. Compatibility studies were also carried by using DSC, which is a qualitative analytical tool for assessing the interactions. The thermograms indicated no substantial amendment in drug endotherm peaks in mixture samples. However, the change in shape and alterations in drugs mixture peak was related to the absorbed moisture by the samples.

Direct compression practice remains engaged to articulate the tablets, since of its cost-clout and owing to reducing the sum of developed strides. The prepared floating tablet, immediate-release tablet and bilayer tablets remain assessed for hardness, weight variation, thickness, friability, drug content uniformity, in vitro disintegration time, buoyancy lag time, total floating time, water uptake (swelling index), in-vitro dissolution studies. The order of floating lag time remain found to be F3<F4<F7<F1<F5<C1<F8<F2<F6. The above results showed such upsurge in the concentration of HPMC K4M upsurges of floating lag time because at high-level HPMC K4M intend perhaps prevent the admittance of medium under the tablet matrix and persist the floating lag period. As proportions of NaHCO 3 upsurges, the floating lag period declines. This spectacle influence is owing to the bearing of more massive extents of effervescence through greater NaHCO 3 proportions. This intend prime to an upsurge in the degree of pore development then subsequently, swift hydration of the tablets matrices. The above order of results showed such upsurge in the concentration of ethyl cellulose results in a decline of floating lag period since of its little bulk density.

The swelling index showed the utmost water uptake, revealed the extreme swelling property. The capacity of hydrogels to engross water is owing to the existence of hydrophilic groups. The hydration of the particular functional groups outcomes in water admittance towards the polymer matrix prominent to extension then subsequently an assembling of the polymer chains.

Entire preparations remain imperilled to five diverse models viz. Zero-order, First order, Higuchi matrix, Peppas model and Hixson-Crowell equations and all the formulations followed Peppas model. The curve fitting consequences of discharge degree contours for the premeditated preparations remain imperilled for data exploration expending PCP-V2 dissolution software. It remains institute that entire the preparations stood fitted into Korsemeyers-Peppas model, which remains the best-fitted model.

The floating, immediate and bilayer tablets were compressed using 9.5mm, 4mm, 9.5mm circular flat-faced punches using RIMEK I multi-station rotary punching machine. Floating property revision exposes that all formulations had suitable floating property. All the formulation floats for more than 12h because the gel layers, designed through the probed polymers, facilitated proficient entrapment of the engendered gas bubbles. Upsurge in concentration of HPMC K4M results in the rise of floating lag time because at high-level HPMC K4M exert probably prevent the access of ways towards the tablet matrix then extend the floating lag period.

As the percentage of NaHCO 3 upsurges, the floating lag time declines. This spectacle potency is owing to the procreation of more significant extents of effervescence through advanced NaHCO 3 proportions. This prime effect to an upsurge in proportion of aperture development then subsequently, swift hydration of the tablets matrices. The above order of results revealed that upsurge in the concentration of ethyl cellulose results in the decline of floating lag period since of its low bulk density. The capacity of hydrogels to captivate water remains owing to the existence of hydrophilic groups. The hydration of the particular functional group outcomes in water admittance towards the polymer complex prominent to extension then accordingly an assembling of the polymer chains.

Based on various evaluation parameters formulation, F4 and A8 were selected as a composition for bilayer floating tablet and was further subjected to in vitro release revision, and stability study. The optimized bilayer floating tablet indicated good stability and values remain inside permitted limits.

5. Conclusion

The strategy of two diverse release phases keep is certainly familiar in together delivery degree and the proportion of the dosage fractions, bestowing to the pharmacokinetics and therapeutic prerequisites. In the immediate-release layer, Indion 414 has a potent effect on in vitro disintegration and in vitro drug discharge. The result of 2 3 full factorial design discovered such as the HPMC K4M, NaHCO 3 and ethyl cellulose concentrations alluringly distress the responses, % CDR, FLT, % Swelling index and T 50%. From the result, it was determined that through assuming a systematic preparation advent, conveyance of two drugs out of a distinct dosage practice could be acquired that might expand bioavailability, patient compliance then provide restored disease supervision.

Declarations

Author contribution statement.

P. Kesharwani: Analyzed and interpreted the data; Wrote the paper.

B. Maddiboyina and M. Hanumanaik: Conceived and designed the experiments; Performed the experiments.

R.K. Nakkala and V. Jhawat: Performed the experiments.

A. Alam, A.I. Foudah and P. Rawat: Analyzed and interpreted the data.

M.M. Alrobaian: Conceived and designed the experiments; Contributed reagents, materials, analysis tools or data.

R. Shukla: Performed the experiments; Contributed reagents, materials, analysis tools or data.

S. Singh: Performed the experiments; Wrote the paper.

Funding statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of interests statement

The authors declare no conflict of interest.

Additional information

No additional information is available for this paper.

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Adaptive Perfusion: A Novel In Vitro Release Testing Method for Complex Ophthalmic Drug Products

2023 FDA Science Forum

Background:

In vitro drug release test is critical for evaluating the product quality of complex drugs, like ophthalmic emulsion drugs. It may be challenging from analytical perspective to test the drug release of complex drug products containing particulates, such as emulsion, suspension, micelles, and liposomes. An ideal in vitro release test (IVRT) should be discriminatory enough to detect the effect of changes in the manufacturing process and variations in product quality on drug release. However, most of the currently available IVRT methods may not be sufficient.

The current work was to show a discriminatory new adaptive perfusion (AP) IVRT method with automated control program that allows investigation of the rate and extent of drug release from complex particulate formulations.

Methodology:

Based on the principle of tangential flow filtration (TFF), the AP method used size-based separation of particulates to simultaneously measure the amount of drug released from and the amount remaining in particulates. A system control program was applied using LabVIEW to achieve the automation of the AP method. In this study, using difluprednate as a model drug, several micelle and emulsion formulations with known variations were manufactured for testing.

The AP method provided discriminatory drug release profiles for the drug substance in solution, in micelles, and in small, medium, and large globule size nanoemulsions. The drug release profile obtained using this system was found to have a significantly faster (e.g., minutes rather than hours) releasing rate and higher releasing extent than the release obtained using conventional dialysis method. With automation, operational procedures were simplified and reduced while maintaining similar results.

Conclusion:

The AP method overcame the limitation of the traditional IVRT method and provided a new approach to study IVRT from complex formulations. With automation, the system simplified the operational procedures, reduced the personnel burden and offers reliable control mechanism, which paves the way for routine use of the AP method for IVRT studies. AP may be used to support bioequivalence and product quality assessment of generic drugs and facilitate new drug product development by giving deeper insight into drug release of complex formulations.

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How Ozempic Is Changing Diabetes Treatment

Millions of patients rely on insulin. But with new drugs, some have been able to lower their doses or stop taking it altogether.

By Dani Blum

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Dani Blum is a health reporter for The Times. More about Dani Blum

What to Know About Diabetes

Diabetes, a condition in which the body has trouble regulating blood sugar, is increasingly common among americans..

Over 37 million Americans have some form of diabetes. Scientists say that medical care  won’t be enough to halt the spread of the disease: Sweeping societal changes are needed .

Insulin resistance can be a precursor to diabetes and pre-diabetes. Here is what to know about the condition and how to know if you have it .

For people with Type 1 diabetes, which often strikes in adolescence, staying healthy can be exhausting . A treatment that can delay the disease’s onset offers some hope .

People who regularly eat red meat may have a higher risk of Type 2 diabetes later in life , according to a new study. Those who often consume processed meats have an even greater risk.

Healthy practices can delay and prevent Type 2 diabetes. Something as simple as going for a 15-minute walk after a meal  could help ward off the disease.

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Reporting by Mariam Sunny and Leroy Leo in Bengaluru; Editing by Tasim Zahid and Sriraj Kalluvila

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GameStop tumbles on capital raise plans after meme-stocks frenzy this week

Retail darling GameStop slumped 26% on Friday after the struggling videogame retailer said it would sell up to 45 million shares, taking advantage of the meme-stocks frenzy this week.

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Viking falls after Roche’s obesity drug data; RayJay upgrades (update)

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Update 2.37 PM EST: Adds details on Raymond James upgrade

Viking Therapeutics ( NASDAQ: VKTX ) was a notable decliner among anti-obesity drug developers on Thursday after Swiss pharma giant Roche ( OTCQX:RHHBY ) said its dual GLP-1/GIP receptor agonist, CT-388, caused roughly 19% average weight loss in a Phase 1 trial.

Shares of San Diego, California-based Viking ( VKTX ) surged in February after its dual GLP-1/GIP receptor agonist VK2735 led to a mean body weight reduction of up to ~15% over 13 weeks in a Phase 2 trial called VENTURE.

While both CT-388 and VK2735 are once-weekly subcutaneous injectables, the former achieved its results over 24 weeks in healthy adults with obesity. However, the VENTURE trial involved overweight or obese adults with at least one weight-related disease.

Citing difficulty comparing data from the two trials and limited safety data for CT-388 from Roche's ( OTCQX:RHHBY ) trial, Raymond James upgraded Viking ( VKTX ) to Strong Buy from Outperform and raised its price target to $116 per share from $115.

Analyst Steven Seedhouse models ~20% unadjusted and ~18% placebo-adjusted weight loss for VK2735 were the patients to receive the drug at 15 mg through Week 24.

Viking ( VKTX ) was also a frequent subject of takeover speculation, most notably linked to Eli Lilly ( LLY ), whose dual GLP-1/GIP receptor agonist Zepbound is a much sought-after weight loss therapy alongside Novo Nordisk's ( NVO ) Wegovy.

However, according to a recent Betaville "uncooked" alert, LLY has paused its efforts to acquire Viking ( VKTX ) over disagreements over price.

More on Viking Therapeutics

• What Makes Viking Therapeutics An Attractive Takeover Target Or Big Pharma Partner
• Viking Therapeutics: The Metabolic Masterpiece Primed To Be Acquired
• Viking Therapeutics, Inc. (VKTX) Q1 2024 Earnings Call Transcript
• Viking Therapeutics down 4% despite quarterly bottom line beat
• Viking Therapeutics gains on early data for oral weight loss therapy

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