Recent Patents on Drug Delivery & Formulation (v.11, #1)

Meet Our Editorial Board Member by Ezharul H. Chowdhury (1-1).

Editorial by Ryan F. Donnelly (2-2).

The challenge of developing a physiologically relevant dissolution test to satisfy regulatory agencies has pushed drug manufacturers to engage in 'design of experiment' method development, which helps manufacturers address variability, dissolution medium, and surfactant use-all of which will influence dissolution.

Background: Probiotics are the live microbes that exert beneficial effects on the health of the host cell, creating novel nanoformulations via probiotic bacteria, thus gaining tremendous momentum recently. The probiotic bacteria are being employed in synthesizing or more specifically biosynthesizing several nanoparticles like metallic as well as non-metallic nanoparticles. Biosynthesis of metallic nanoparticles is currently the focus of research nowadays due to several applications. Research inputs have led to the exploration of probiotic bacteria in biosynthesizing novel metallic nanoparticles.
Objective: The present review explores various research and patent reports on metallic nanoparticles biosynthesized using probiotic bacteria.
Method: Through the sites, and, patents have been retrieved including US patents, EP and WIPO patents.
Results: Various reports and patents have revealed that probiotic bacteria can effectively produce metallic nanoparticles. These nanoparticles have found applications in cosmetics, pharmaceutics, medicine and biotechnology. Areas of future research can include the exploration of formulation aspects of metallic nanoparticles of iron, zinc, tellurium and synthesis of these particles using yeast, fungi, plant extracts and several biomaterials.
Conclusion: Use of probiotic bacteria in synthesizing metallic nanoparticles is an effective biosynthetic approach. However, the technique needs wider exploration for newer metallic/nonmetallic/metalloid NPs for therapeutic applications.

Formulation Development and Optimization of Matrix Tablet of Tramadol Hydrochloride by Pulak Deb, Jubaraj Singha, Indranil Chanda, Prithviraj Chakraborty (19-27).
Background: The aim of the present investigation is to formulate and optimize oral sustained release matrix tablet of highly water soluble drug Tramadol HCl and to evaluate the effect of varying concentration of hydrophilic and hydrophobic polymer on drug release, based on a survey done on the recent patents of Tramadol HCl (US7374781, CA 2479252) and sustained release matrix tablets.
Methods: The tablets were prepared by double granulation process, by melt granulation and wet granulation technique using Carnauba wax (CW) and HPMC K100 as release retardant.
Results: Pre and post compression factors were evaluated and all the parameters were found within the limit. The drug release data were subjected to different models in order to evaluate release kinetics and mechanism of drug release. The prepared formulations showed drug release in the range 100A±2% in 6hrs, 7hrs, 8hrs and 9hrs and upto 12 hrs respectively. The optimized tablet having 25% CW and 20% HPMC showed sustained drug release pattern. Hydrophilic matrix of HPMC alone could not control the Tramadol release effectively for 12 h whereas when combined with CW could slow down the release of drug and can be successfully employed for formulating sustained-release matrix tablets. Similarity factor, f2 shows the test and reference profile are identical.
Conclusion: Double granulation technique with CW and HPMC K100 proved as a better technique for sustaining the drug release from the matrix tablet.

Background: The absorption of drug through skin avoids many side effects of oral route like gastric irritation, nausea, systemic toxicity etc and thus improves patient compliance. Naproxen sodium (NPRS) is one of the potent NSAID agents.
Objective: The present study was aimed to develop and evaluate the gel formulation containing NPRS for transdermal drug delivery reducing the side effects and improving patient compliance. The patents on topical delivery of NSAIDS (US 9012402 B1, US 9072659 B2, US 20150258196 A1) and patents indicating use of herbal penetration enhancers (US 20100273746A1, WO 2005009510 A2, US 6004969 A) helped in selecting the drug, excipients.
Method: Current protocol employs various extracts of Piper cubeba fruit to evaluate its role in absorption of NPRS. Various batches containing 1% NPRS and varying concentrations of synthetic permeation enhancers or the extracts were formulated in carbopol gel. Gel was evaluated for parameters like organoleptic parameters, pH, viscosity and spreadability. An ex-vivo percutaneous absorption of NPRS from gel was investigated and compared with best performing synthetic enhancer, transcutol P (TP).
Result: The batch containing 2% n-hexane extract (NHE) of Piper cubeba showed higher permeation than TP and Chloroform (CE), Methanolic (ME) and aqueous (AE) extracts as well. It showed improved % cumulative release (85.09%) and flux (278.61μg/cm2.h), as compared to TP and other extracts. Histopathology indicated the formulation safer as compared to that with synthetic enhancer.
Conclusion: It suggests P. cubeba as effective and safer tool for transdermal delivery and acts as therapeutic facilitator for naproxen. GC-MS analysis indicates lignans & terpenes in NHE to which this permeation enhancement activity may be attributed.

Anti-Psychotic Activity of Aqueous Root Extract of Hemidesmus indicus: A Time Bound Study in Rats by Ashwathanarayana Madhu, Gaurav Gupta, Bharati Arali, Dinesh K. Chellappan, Kamal Dua (36-41).
Aims and Background: Psychosis is a neurological disorder, which is usually defined as the "loss of contact with reality." As medicine 'Hemidesmusindicus' holds a reputed place in all systems of medicine in India. It is given in the form of infusion, fine particles, or syrup. It is also a component of several medicinal preparations. The present research work is pertaining to find out an anti-psychotic activity of an aqueous root extract of Hemidesmusindicus- a time bound study in rats.
Methods: In the present study, the dried roots of Hemidesmusindicus were crushed to a coarse powder and extracted with water under reflux for 36 hours to obtain the aqueous extract of roots of Hemidesmusindicus (AERHI). The extract was reconstituted in 2% aqueous tragacanth just before use and administered orally at a dose 0f 100 mg/kg, 300 mg/kg and 500 mg/kg. In a single dose study, the parameters were assessed after oral administration of the single dose of the AERHI, whereas in a multiple dose study, the animals daily received the suitable oral dose of the AERHI for a period of 30 days. The parameters were assessed on the 15th and 30th day. The antipsychotic activity was screened using Apomorphine induced Stereotyped behavior in rats and Haloperidol induced catalepsy models were used. In Apomorphine induced Stereotyped behavior inhibition of the Stereotyped behavior was considered to be anti-psychotic activity and in Haloperidol induced catalepsy, we observed whether the AERHI potentate or attenuate the catalepsy in rats.
Results: In this study, the extract of Hemidesmusindicus significantly inhibited the stereotyped behavior induced by apomorphine in rats and also potentiate the catalepsy induced by haloperidol, thereby showing its anti-psychotic activity.
Conclusion: All these observations imply that Hemidesmusindicus extract possesses anti-psychotic activity in experimental animals.

Background: Nasal inserts are novel, solid, bioadhesive dosage forms administered via nasal route for prolonged systemic drug delivery. The principle of the dosage form is that, after administration nasal inserts imbibe nasal fluid from the mucosa and form a gel in the nasal cavity in order to avoid foreign body sensation. The objective of this investigation was the development of chitosan/xanthan gum based bioadhesive nasal inserts of antimigraine drug.

Methods: Lyophilization is more usual technique for the preparation of nasal inserts and it is one of the applied methods for drying of solids either in the form of aqueous solution or rarely in the form of aqueous suspension by using freeze dryers. The recent patents on Biocompatible polymer (US20140301972A1), High molecular weight polymers (US20050048121A1), Migraine treatment (WO2009080764A3) helped in selecting the drug and polymers. A 32 factorial design was used to investigate the combined effect of two independent variables such as concentration of Xanthan gum (X1) and the concentration of Chitosan (X2), onto the water uptake, bioadhesion potential and drug release which were the dependent variables. Nine batches of the nasal inserts were developed and evaluated for water uptake at three different pH, bioadhesion potential and drug release. The optimized nasal inserts batch was also characterized by DSC, PXRD and SEM.

Results: The results showed that the water uptake ability of nasal insert was strongly influenced by pH of the medium and by polycation/polyanion concentration. This investigation verifies the formation of complexes between chitosan and xanthan gum and confirms the potential of these complexes, in achieving the sustained antimigraine drug delivery in the nasal cavity.

Conclusion: The best nasal inserts formulation containing chitosan and xanthan gum in the ratio 0.5:0.5, showed desirable % drug release as well as bioadhesion which may result in an increase in the nasal residence time.

Background: In the present study, Lansoprazole pellets were prepared employing a novel excipient Carboxymethyl tamarind kernel powder (CMTKP) using extrusion-spheronization technique. Various research studies including patents have been carried out on this polymer. Pellet formulation was optimized for formulation parameters (concentration of microcrystalline cellulose, CMTKP, croscarmellose sodium and isopropyl alcohol).
Methods: Process parameters (speed and duration of spheronization) were optimized using factorial design. The pellets were evaluated for yield, bulk and tapped density, particle size, hardness, drug content, disintegration time and drug release.
Results: The optimized batch showed 93.53% yield, 0.307 kg/cm2 hardness, 2.15 mm average particle size, 292 sec disintegration time and 90.46% drug content.
Conclusion: Drug release of the optimized batch (2F7) and marketed formulation (LANZOL cap) was found to be 82.33% and 80.07%, respectively. An accelerated study indicated that optimized formulation was stable.

Background: To develop pulsatile microspheres of Nifedipine blend of polymers Carbopol 971P and Eudragit RS100 for antihypertensive to release the drug at a particular lag time.

Methods: Pulsatile nifedipine microspheres were prepared using the blend of Carbopol 971P and Eudragit RS100 at different ratios in a mixture of solvents. Formulations were prepared and optimized on the basis of particle size, percentage yield and drug entrapment efficiency. Optimized formulations were further analyzed at different resolutions per minute (rpm) by optical microscopy, scanning electron microscopy (SEM), in-vitro dissolution studies and kinetics model. The most promising formulation was compared with the marketed products. The recent patents on microsphere used for hypertension for drug used Liensinine (CN104757561). Dopamine antagonist (US20030069232A1), Human Serum Albumin (EP19990304616) and Omeprazole (IN2107/DEL/2014) helped in selecting the drug and polymers.

Results: The formulated microspheres had mean particle size ranging from 177.31 to 277.48 µm. Formulation F83 showed slow release of drug initially for 4 h and drastically release of drug enhanced at a particular lag time (Showed pulsatile release) after 6 h. However, conventional marketed products showed maximum release initially at 1 h and decreased gradually while controlled released marketed product showed sustained pattern.

Conclusion: On the basis of data formulation F83 showed slow release and at a particular lag time followed by pulsatile release pattern and followed first order kinetics model. It was concluded that the formulated nifedipine pulsatile dosage form could be useful in the treatment of hypertension.

Patent Selections by .. (77-80).