FIXED-DOSE COMBINATION TABLETS

Nebivolol/valsartan fixed-dose combination exhibited good therapeutic when continued for 52 weeks. The novel dose combination exhibited a significant lowering of blood pressure (BP) than the monotherapy. It was further subsumed that the combination decreased plasma renin and aldosterone levels (Battise et al., 2018).

Hyperuricemia in patients with uncontrolled gout was a recently once- daily combination of lesinurad and allopurinol. It was suggested clinically that the target serum uric acid (SUA) levels in patients which were not achieved by allopurinol alone. The FDC has also approved the combination (Barrett, 2017).

UNIQUE PULSATILE RELEASE

Pulsatile drug delivery provides spatial that is time-specific drug delivery and temporal that is site-specific drug delivery system. The system is unique as it involves a rapid and transient release of a certain amount of molecules immediately after the lag time period, and also these systems have the ability to deliver the drug rapidly and completely after a lag time period. Pulsatile delivery system is achieved via hydrogel technique, microchip teclmique or also through implant system. Hydrogels beads can be a good source for solid oral dosage form delivery (Jain et al., 2011; Kikuchi and Okano, 2002; Prescott et al., 2006; Santini et al., 2000).

Time-controlled pulsatile release (PR) formulation to facilitate the management of early morning chronological attacks can be achieved by using a direct compressed prednisone tablet coated in ethylcellulose (EC)-hydroxypropyl methylcellulose (HPMC) excipient blend. The tablet exhibited a lag time of 4-6 hrs by burst release profile under variegated dissolution conditions. The outcome was achieved as desired using the pulsatile system (Patadia et al., 2017).

Decrease in the lag time was observed from HPMC press-coated EC tablets of prednisone. Delay in the lag time was pronounced by the molecule weight of HPMC. It was evident that low MW HPMC was more effective than the high MW of HPMC (Patadia et al., 2016).

Patented technique pulsincap was used to design 5-fluorouracil osmogene filled capsules. The successful circadian rhythm was exhibited to target the drug to colorectal carcinoma according to daily oscillations of rate-limiting metabolizing enzyme dihydropyrimidine dehydrogenase (Patel et al., 2011). Novel diffucaps technology was applied to characterize the pharmacokinetic profiles of oral extended-release methylphenidate products (Yang et al., 2016).

A divisible pharmaceutical tablet comprises two portions: the upper and the lower portion. The upper portion has an upper convex surface bordering at least one dividing notch. Such tablets are characterized by dispensing a pharmaceutical composition to the patients in a measured, predetermined dose (Parikli et al., 2011).

Ketoprofen and ibuprofen pellets fabricated using eudragit and ethyl cellulose demonstrated a chronotherapeutics pattern of drug release extended for 22 h depending on the concentration of ethyl cellulose (Dumpa et al., 2018).

Researchers have successfully demonstrated the pharmaceutical use of cassava starch nanocrystals. The cassava starch nanocrystal could lower the mechanical properties of the ethylcellulose film, and also decreases lag time-sensitivity of the ruptured coating, which provides an excellent pulsatile release system (Charoenthai et al., 2018).

An innovative dual delivery system based on a tablet-in-tablet providing a two-pulse release of rivastigmine with a time difference of 6.5 h between the peaks of the pulses (Penhasi and Gomberg, 2018).

SOLID SELF EMULSIFYING DRUG DELIVERY SYSTEM

Approximately 40% of new drugs, exhibit poor aqueous solubility and low bioavailability. A novel technique, self-emulsifying drug delivery systems (SEDDS) intended to increase solubility and oral bioavailability of drugs having poor biopharmaceutical properties (Gurudutta et al., 2010).

Conventional SEDDS, however, are mostly prepared in a liquid form, which can produce some disadvantages. Appropriate excipients, solid earners, and processing parameters must be selected for each solidification technique to enable process-ability and preserve the self-emulsifying ability of the system upon its transfonnation into the solid formulation (Mandic et al., 2017; Tang et al., 2008).

The solid SEDDS of dexibuprofen powder gave significantly higher AUC and Cniax than dexibuprofen powder (P < 0.05). The results showed that AUC of solid SEDDS was about twofold higher than that of dexibuprofen powder (Balakrishnan et ah, 2009).

Liquid lipid-based self-emulsifying drug delivery systems (SEDDS) can be converted into solid dosage forms by adsorbing onto silicates. Probucol was dissolved in liquid SEDDS containing different lipid to surfactant ratios, and the formulations were then adsorbed onto equal weights of silica. The fonnulation showed the desired release even after 6 months of storage period confirming the viability of SEDDS to be used as a solid dosage form for probucol (Gumaste and Serajuddin, 2017).

Griseofulvin-SEDDS addition to silica was fonnulated by Agarwal et ah They deduced that special attention should be given to particle size, specific surface area, type and amount of adsorbent since it will affect the drug release characteristics of the active ingredient (Agarwal et ah, 2009).

Poorly soluble nitrendipine (NTD) was formulated as the new solid self-emulsifying (SE) spheronized pellets. The SE pellets with 30% liquid SEDDS exhibited uniform size, the oral bioavailability of new SE pellets showed a 1.6-fold increase than the conventional tablets (Wang et ah, 2010).

Celastrol, a chemical compound isolated from the root extracts of Tripterygium wilfordii which is known to have anti-inflammatory and anticancer properties. Oral bioavailability of celastrol is calculated as very low. SEDDS may be a suitable technique to increase the oral bioavailability of celastrol. The optimized fonnulation of celastrol-SMEDDS dispersible tablets could disperse in the dispersion medium within 3 min with the average particle size of 25.32 ± 3.26 mn. In vivo pharmacokinetic experiments on rats, suggest the potential use of SEDDS dispersible tablets for the oral delivery of poorly water-soluble terpenes drugs, such as celastrol (Qi et ah, 2014; Zhang et ah, 2012).

Studies suggest that adsorption teclmique, spray-diying process, high- shear granulation, fluid-bed granulation can be used for preparing solid SEDDS powders by using solid carriers. Naproxen SEDDS using different solidification techniques and carriers had considerable influence on the dissolution profile and solubility enhancement of naproxen. It is advised to use appropriate solidification and compression teclmique to formulate SEDDS tablets (Cerpnjak et al., 2015).

Ibuprofen SEDDS pellets containing Neusilin derivatives were formulated by a fluid bed coating process. Dissolution studies showed that from the formulation composed of 70 wt.% of Neusilin SG2 after 45 min, more than 75% of ibuprofen was dissolved in water and after 30 min, more than 80% of ibuprofen was dissolved in the phosphate buffer (Krupa et al., 2014). Similar trials were done for risperidone, using NSU2. The characterization results showed that NUS2 yield superior flowability of the powder. The SEM revealed that pure risperidone was in irregular crystal shape whereas the drug-loaded solid SEDDS were in smooth regular shape. From the dissolution studies, it was found that solid SEDDS provided significant release profiles (>95%) compared to marketed product risp- erdal® (Kazi et al., 2017). Dissolution and bioavailability of flurbiprofen were also improved by a solid self-nanoemulsifying drug delivery system (solid SNEDDS) (Kang et al., 2012). Glipizide dissolution improved significantly (p < 0.001) from the solid SNEDDS (~ 100% in 15 min) as compared to the pure drug (18.37%) and commercial product (65.82%) respectively (Dash et al., 2015).

COCRYSTALS

The pharmaceutical solvates, polymorphs, hydrates, amorphous forms are presented as a one-component system. The two-component system to host drug molecules is called co-crystals (Figure 3.3). These solid forms play a vital role in drug discovery and development in the context of optimization of bioavailability, filing intellectual property rights (Healy et al., 2017; Pankaj Sharma, 2011). The pharmaceutical co-crystals bonded by hydrogen binding helps to optimize physiochemical, pharmaceutical and biological properties of drug molecules (Douroumis et al., 2017; Pindelska et al., 2017; Malamatari et al., 2017). Deep idea of pharmaceutical multicomponent phase design, the intermolecular interactions are desired to formulate co-crystals. These newer systems have the tendency to vary material properties and pharmacokinetics in a patient (Berry and Steed, 2017).

Schematic diagram of co-crystals (Reprinted with permission from Korotkova and Kratochvil, 2014. © Elsevier.)

FIGURE 3.3 Schematic diagram of co-crystals (Reprinted with permission from Korotkova and Kratochvil, 2014. © Elsevier.)

The design of co-crystals was carried out by a CC analysis program, />-DISOL-X. Various acid-base combinations of active pharmaceutical ingredients (APIs) and co-formers: (i) carbamazepine cocrystal systems with 4-aminobenzoic acid, cinnamic acid, saccharin, and salicylic acid, (ii) for indomethacin with saccharin, (iii) for nevirapine with maleic acid, saccharin, and salicylic acid, and (iv) for gabapentin with 3-hydroxyben- zoic acid were designed using the system. The carbamazepine-cinnamic acid CC showed a substantial elevation in the API equilibrium concentration above pH 5, consistent with the formation of a complex between carbamazepine and cinnamate anion. The analysis of the gabapentin: 3-hydroxybenzoic acid 1:1 CC system indicated four zones of solid suspensions: coformer (pH < 3.25) and cocrystal eutectic (pH 3.25-4.44), cociystal (pH 4.44-5.62), and API (pH > 5.62). The general approach allows for testing of many possible equilibrium models, including those comprising drug-coformer complexation (Avdeef, 2017).

Lamotriginenovel cocrystals were designed using 4,4'-bipyridine (2:1) and 2,2'-bipyridine as coformers. Cocrystal was successfully characterized by X-ray diffraction, thermal and spectroscopic analysis, Raman microscopy, the in vitro dissolution rate and the solubility of the two novel cocrystals were significantly improved (Du et al., 2017).

4-aminosalicylic acid (PASA) was crystallized with a number of coformers [pyrazinamide (PYR), nicotinamide (NAM), isonicotinamide (iNAM), isoniazid (INH), caffeine (CAF), and theophylline (TPH)]. The new co-crystallized have exhibited unproved solubility and higher stability against the chemical decomposition (Drozd et al., 2017).

INNOVATIVE ORODISPERSIBLE DOSAGE FORMS

Orodispersible dosage forms based on polymeric matrices have currently demonstrated their prominence in accordance with the actual market requirements and patients’ demands. Oral lyophilisates and orodispersible granules, tablets or films have enriched the therapeutic options (Borges et ah, 2015); Slavkova and Breitkreutz, 2015; Tahir et ah, 2010).

Innovative Flexible oral dispersible system, orally swallowable, orally disintegrating, chewable tablets have certainly increased patient compliance. Pediatric and geriatric patients are preferring novel sprinkle formulations such as pellets, granules packed in capsules or sachets are conveniently used by (Chandrasekaran and Kandasamy, 2018).

Cetirizine, polacrilex ratio of 1:2 to 1:3 showed strong physical strength and an intensely rapid in vitro dispersion within 30 s in 2-6 ml of water. Polacrilex resin with taste-masking effect and improved stability exhibited immediate drug release within 30 min in gastric media. This is a novel process of formulating ion exchange resins based on solid oral flexible drug products (Chandrasekaran and Kandasamy, 2017).

Pre-formed resinate of cetirizine HC1 cyclodextrin complexes was incorporated into the Zydis® oral lyophilisate technology. It was evident that taste was effectively masked for the designed formulation (Preis et ah, 2015).

 
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