TECHNICAL FIELD

[01] The present disclosure relates to a solid pharmaceutical dosage form, and more particularly to a solid orally-disintegrating tablet that includes one or more active ingredients and at least one chitosan (“CS”) ionic salt as an excipient.

BACKGROUND

[02] An interesting class among oral tablets is the oral disintegration tablets or sometimes referred to as orodispersible tablets (“ODT”). Such tablets at least partially disintegrate totally inside the mouth cavity without the need for water. ODT are becoming increasingly popular worldwide and usually serves as an alternative dosage form for patients experiencing difficulty in swallowing (for example, as a result of Dysphagia). Dysphagia is common in all ages, observed in about 35% of the total population, and may reach up to 60% in the elderly population. In addition, many patients prefer to use ODT due to the ease of product intake. These ODT products have less effort in their administration and may be more preferable by certain patients than traditional tablets.

[03] Disintegration rate and robustness of ODT are considered to be important issues for success. In order to achieve rapid disintegration rates of ODT, such tablets should have high porosity, low density, and low hardness. Manufacturing techniques used in order to obtain such properties include lyophilization and moulding. However, such techniques produce brittle tablets, which require special equipment for packaging. Direct compression is another technique used for ODT production. It is simple, cost effective, and results in hard tablets with rapid disintegration rates when proper excipients are used.

[04] In previous studies, researchers focused on the use of a multi-component excipient mixture to develop ODT, where a blend of compressible filler, a super-disintegrant, and a lubricant were combined. These components were used with each other to facilitate the production and pharmaceutical function of the ODT. All the components were mixed with the active ingredient and compressed by a direct compression method. Some recently-developed excipients replaced the multi-component mixtures. Such excipients are co-processed in a ready-made powder. Other co-processed excipients include binary systems of hydrophilic polymers and silica or silicates.

[05] Chitosan silicate is a co-processed excipient composed of two different chemical entities processed by co-precipitation of silicates onto CS to have high disintegrating rates. However, there are some disadvantages associated with chitosan silicate preparations. For example, the production process involves tedious work, as it involves the inclusion of a chemically different material within the structure of CS, and a use of a large amount of costly materials, as well as much expenditure of energy. Furthermore, mechanical properties of such co-processed excipients are strongly dependent on moisture content, particle size, and powder bulk density.

SUMMARY

[06] Aspects of the present disclosure provide a solid orally-disintegrating tablet that includes one or more active ingredient and at least one CS ionic salt as an excipient.

[07] In some aspects, CS may be cross-linked with one or more multivalent anions in the at least one CS ionic salt.

[08] The at least one CS ionic salt may include divalent and/or trivalent anions.

[09] In aspects of the present disclosure, the at least one CS ionic salt may be selected from a group containing CS carbonate, CS sulfate, and CS phosphate.

[010] In other aspects, the tablet of the present disclosure may further include flavorings, lubricants, colorings, sweeteners, or a combination thereof.

[Oil] In aspects of the present disclosure, the one or more active ingredients is selected from bromopride, metoclopramide, cisapride, domperidone, aceclofenac, diclofenac, flubiprofen, ibuprofen, sulindac, celecoxib, acetaminophen, aspirin, sildenafil, apomorphine, sumatriptan, ergotamine, loratadine, fexofenadine, cetirizine, nitroglycerine, isosorbide dinitrate, furocemide, spironolactone, propranolol, amlodipine, felodipine, nifedipine, captoprile, ramiprile, atenolol, diltiazem, simvastatin, atorvastatin, pravastatin, cimetidine, ranitidine, famotidine, omeprazole, lansoprazole, meclizine hydrochloride, ondansetron, granisetron, ramosetron, tropisetron, aminophylline, theophylline, terbutaline, fenoterol, formoterol, ketotifen, fluoxetine and sertraline, vitamin Bl, vitamin B2, vitamin B6, vitamin B12, vitamin C, sulfinpyrazone, dipyridamole, ticlopidine, cefaclor, bacampicillin, sulfamethoxazole, rifampicin, dexamethasone, methyltestosterone, piperazine, ivermectine, mebendazole, acarbose, gliclazid, glipizide, or salts thereof.

[012] In some aspects, the one or more active ingredients may include Ibuprofen lysinate.

BRIEF DESCRIPTION OF THE DRAWINGS

[013] The disclosure will now be described with reference to the accompanying drawings, which illustrate embodiments of the present disclosure, without however limiting the scope thereof, and in which:

[014] FIG. 1A illustrates a chemical interaction between CS and a carbonate ion in an orally- disintegrating tablet configured in accordance with embodiments of the present disclosure.

[015] FIG. IB illustrates a chemical interaction between CS and a phosphate ion in an orally- disintegrating tablet configured in accordance with embodiments of the present disclosure.

[016] FIG. 1C illustrates a chemical interaction between CS and a sulfate ion in an orally- disintegrating tablet configured in accordance with embodiments of the present disclosure.

[017] FIG. 2 illustrates a flow chart of a system and method for preparing CS salts in accordance with embodiments of the present disclosure.

[018] FIG. 3 illustrates a comparison of Fourier-transform infrared spectroscopy (“FTIR”) plots of CS salts prepared in accordance with embodiments of the present disclosure, wherein“CS-S” represents CS Sulfate salt,“CS-C” represents CS carbonate salt,“CS-P” represents CS phosphate salt, and“CS” represents CS.

[019] FIG. 4 illustrates a comparison of differential scanning calorimetry (“DSC”) plots of CS, CS sulfate salt, CS carbonate salt, and CS Phosphate salt, wherein“CS-S” represents CS Sulfate salt,“CS-C” represents CS carbonate salt,“CS-P” represents CS phosphate salt, and“CS-H” represents CS HC1. [020] FIG. 5A shows a scanning electron microscope (“SEM”) image of CS used in embodiments of the present disclosure, wherein the image scale is 100 pm.

[021] FIG. 5B shows an SEM image of CS carbonate salt used in embodiments of the present disclosure, wherein the image scale is 100 pm.

[022] FIG. 5C shows an SEM image of CS phosphate salt used in embodiments of the present disclosure, wherein the image scale is 100 pm.

[023] FIG. 5D shows an SEM image of CS sulfate salt used in embodiments of the present disclosure, wherein the image scale is 200 pm.

[024] FIG. 6 illustrates a column chart comparing moisture uptake of CS salts prepared in accordance with embodiments of the present disclosure at different relative humidity levels, wherein“chitosan” represents CS,“CS-S” represents CS sulfate salt,“CS-C” represents CS carbonate salt, and“CS-P” represents CS phosphate salt.

[025] FIG. 7 illustrates a column chart comparing water sorption ratios of CS salts prepared in accordance with embodiments of the present disclosure after exposure to water for 5 minutes, wherein“chitosan” represents CS,“CS-C” represents CS carbonate salt,“CS-P” represents CS phosphate salt, and“CS-S” represents CS sulfate salt.

[026] FIG. 8A illustrates a plot comparing Ibuprofen lysinate release behavior obtained experimentally versus a predicted behavior when used with CS in accordance with embodiments of the present invention, wherein“EXP” represents experimentally obtained behavior, and wherein “PRED” represents predicted behavior.

[027] FIG. 8B illustrates a plot comparing Ibuprofen lysinate release behavior obtained experimentally versus a predicted behavior when used with CS carbonate salt prepared in accordance with embodiments of the present invention, wherein“EXP” represents experimentally obtained behavior, and wherein“PRED” represents predicted behavior.

[028] FIG. 8C illustrates a plot comparing Ibuprofen lysinate release behavior obtained experimentally versus a predicted behavior when used with CS sulfate salt prepared in accordance with embodiments of the present invention, wherein“EXP” represents experimentally obtained behavior, and wherein“PRED” represents predicted behavior.

[029] FIG. 8D illustrates a plot comparing Ibuprofen lysinate release behavior obtained experimentally versus a predicted behavior when used with CS phosphate salt prepared in accordance with embodiments of the present invention, wherein“EXP” represents experimentally obtained behavior, and wherein“PRED” represents predicted behavior.

DETAILED DESCRIPTION

[030] The term“solid pharmaceutical dosage form” as used herein means any preparation in the form of tablets that are obtained by densification of a powder. These solid dosage forms include inert materials grouped under the term of excipients, and one or more pharmaceutical active substances.

[031] The term “orally-dispersible tablet” as used herein means solid dosage forms that disintegrate in the buccal cavity in less than about 3 minutes.

[032] The term“excipient” as used herein refers to any pharmaceutical additive material that is used in the pharmaceutical dosage form other than the one or more pharmaceutical active substances.

[033] As used in this specification, the term“predicted behavior” refers to a pattern obtained by simulation.

[034] As used in this specification, the term“release behavior” refers to a release pattern as expected by doing several statistical iterations by using a computer software to compare equation fitness to real experimental data.

[035] Embodiments of the present disclosure provide a solid orally-disintegrating tablet that includes one or more active ingredients and at least one CS ionic salt as an excipient.

[036] In accordance with embodiments of the present disclosure, CS ions may be cross-linked with one or more multivalent anions in the at least one CS ionic salt. [037] In embodiments of the present disclosure, the at least one CS ionic salt may include divalent and/or trivalent anions.

[038] The at least one CS ionic salt may be selected from a group containing CS carbonate, CS sulfate, and CS phosphate.

[039] The orally-dispersible pharmaceutical formulation in embodiments of the present disclosure is made of compacted powder particulate of a cross-linked CS polymer. The disintegration characteristics are obtained as a result of crosslinking of the hydrophilic backbone of the CS polymer. Cross-liking resulted in the formation of highly porous water-insoluble microstructures. Thus, more water is absorbed by capillary action to the intimate structure of powder particle which is the building unit of the solid formulation. Absorbed water enhances unequal swelling of each powder particulate within the structure of the solid formulation. Consequently, such effect will result in rapid disintegration characteristics of the compact.

[040] Reference is now being made to FIGS. 1A-1C, which illustrate chemical interactions between CS ions and multivalent anions, namely carbonate ions (FIG. 1 A), phosphate ions (FIG. IB), and sulfate ions (FIG. 1C). CS ions are cross-linked with such ions, wherein the crosslinking is mainly driven via ionic interaction of the multivalent anions with the positively charged primary amino groups present in the glucosamine monomers of a CS ion (salt-bridge interactions). FIG. 1A illustrates a chemical interaction between a CS ion and a carbonate ion in an orally- disintegrating tablet configured in accordance with embodiments of the present disclosure. FIG. IB illustrates a chemical interaction between a CS ion and a phosphate ion in an orally- disintegrating tablet configured in accordance with embodiments of the present disclosure. FIG. 1C illustrates a chemical interaction between a CS ion and a sulfate ion in an orally-disintegrating tablet configured in accordance with embodiments of the present disclosure.

[041] The solid orally-disintegrating tablet in embodiments of the present disclosure may optionally further include flavorings, lubricants, colorings, sweeteners, or a combination thereof.

[042] In embodiments of the present disclosure, the one or more active pharmaceutical substances may be selected from bromopride, metoclopramide, cisapride, domperidone, aceclofenac, diclofenac, flubiprofen, ibuprofen, sulindac, celecoxib, acetaminophen, aspirin, sildenafil, apomorphine, sumatriptan, ergotamine, loratadine, fexofenadine, cetirizine, nitroglycerine, isosorbide dinitrate, furocemide, spironolactone, propranolol, amlodipine, felodipine, nifedipine, captoprile, ramiprile, atenolol, diltiazem, simvastatin, atorvastatin, pravastatin, cimetidine, ranitidine, famotidine, omeprazole, lansoprazole, meclizine hydrochloride, ondansetron, granisetron, ramosetron, tropisetron, aminophylline, theophylline, terbutaline, fenoterol, formoterol, ketotifen, fluoxetine and sertraline, vitamin Bl, vitamin B2, vitamin B6, vitamin B12, vitamin C, sulfinpyrazone, dipyridamole, ticlopidine, cefaclor, bacampicillin, sulfamethoxazole, rifampicin, dexamethasone, methyltestosterone, piperazine, ivermectine, mebendazole, acarbose, gliclazid, glipizide, or salts thereof.

[043] Embodiments of the present disclosure are now further illustrated on the basis of Examples and a detailed description from which further features and advantages may be taken. It is to be noted that the following explanations are presented for the purpose of illustrating and description only; they are not intended to be exhaustive or to limit the disclosure to the precise forms disclosed.

Example 1

Preparation of CS ionic salts Materials

[044] Chitosan (CS) HC1 was commercially obtained from Himedia Laboratories PVt Ltd, India. Sodium sulfate was commercially obtained from Sigma Aldrich, U.S.A. Sodium carbonate anhydrous PRS was commercially obtained from Panreac Quimica S.A.U., Spain. Tri-sodium phosphate 1 -hydrate PRS was commercially obtained from Panreac, Spain. Microcrystalline cellulose, average particle size 50 pm, was commercially obtained from Across Organics, New Jersey, U.S.A. Other reagents and chemicals were of analytical grade.

Preparation Scheme

[045] Reference is now being made to FIG. 2, which represents a flow chart of a system and method for preparing CS sulfate salt. An amount of 10 g of CS HC1 (“CS-H”) was dissolved in 400 ml of distilled water (process block 2-1). The solution was equally divided into three sets of “CS-H” solutions, and three different amounts of sodium sulfate were gradually added to the three sets of“CS-H” solutions and homogenized (process block 2-2), wherein the concentrations of sodium sulfate to“CS-H” CS in the three different sets were 40%, 60%, and 80% weight/weight (“w/w”), respectively. Then, 500 ml of ethanol was added to each of the CS/sodium sulfate mixtures to enhance precipitation (process block 2-3). After that, each of the precipitated mixtures were filtered using a Buchner filtration unit, and the three different precipitates, CS sulfate (“CS- S”), were washed with ethanol (50% weight/volume (“w/v”)) to remove any soluble salts (process block 2-4). The“CS-S” precipitates in each set were dried in an oven at about 75°C for about 12 hours, and then stored in desiccators until used (process block 2-5).

[046] A similar procedure as described above was utilized to prepare CS phosphate (“CS-P”) and CS carbonate (“CS-C”) precipitates.

Example 2

Tablet preparation

[047] In order to prepare solid tablet dosage forms with optimum disintegration time, two factors should be assessed; the concentration of anionic salt used during CS crosslinking, and the applied compression pressure.

[048] A software program, Design-Expert DX9 for design of experiments (“DOE”), version 9, commercially available from Stat-Ease Inc., U.S.A., was used to optimize the process using response surface methodology (“RSM”), a statistical approach that explores the relationship between several explanatory variables with one or more response variables using factorial experiments in a polynomial model.

[049] Two variables could affect the disintegration of tablets: the amount of salt added to crosslink the CS ions, and the compression pressure used to form a tablet. Two consequent responses were evaluated (i.e., disintegration time and tablet elastic ratio).

[050] In order to optimize the conditions of interaction with CS ions,“RSM” of the three ionic salts (carbonate, phosphate, and sulfate) were evaluated for the optimal concentration of salt, and optimal compression pressure that could result in tablet elasticity described as elastic ratio, and disintegration rate described in terms of disintegration time. Central composite, an experimental design used in RSM for building quadratic model without the need to use three level factorial experiment, of fourteen runs of two blocks with quadratic polynomial model was carried out. Concentration of salts (40-80% w/w) and compression pressure (100-140 MPa) were analyzed taking into consideration the response constraints of a lower limit of the target detected by the “RSM,” while keeping the concentration of salts and compression pressure in the mentioned ranges.

Elastic ratio

[051] In order to determine the elastic ratio, compression was carried out using a press (model 3367, commercially available from Instron Ltd, U.S.A.). The weighed samples, each 0.5 g, were filled in a circular 15 mm die. A software program (Bluehill ^® 2, version 2.31, commercially available from Hotfix) for the press was adopted using a compression extention mode with a maximum compression of 2500 kgf. The powder was compressed down with a rate of about 10 mm/minute until reaching the pressure in the range of about 100-140 MPa in the compression stage, and the cross-head was lifted up until a zero pressure was obtained in the decompression stage.

Disintegration time

[052] Circular Compact, i. e. a circular tablet formed by compression of a powder bed in a circular die using suitable compression pressure, (of about 15 mm diameter) was prepared of different CS cross-lined ions of various concentrations (in the range of 40-80% w/w) at compression pressure ranges of 100-140 MPa. Disintegration behavior was assessed using a disintegration tester (QC- 21 disintegration test system, commercially available from Hanson Research, U.S.A.) in distilled water at about 37±0.5°C. The disintegration time of the circular compacts of (n=3) was recorded during the test period, wherein“n” is the number of repeated experiments.

[053] A selection of optimal concentrations factors that have the best effect on disintegration time and elastic ratio was carried out using“RSM.” The obtained optimal tablets were prepared and characterized. RSM software determines the optimal concentrations and compression force as explanatory factors that should be used to get the best effect (response) of disintegration i.e. lowest disintegration time.

[054] The central composite design used for the preparation of CS salts using the compression pressure and the concentration of salts versus the elastic ratio and disintegration time is summarized in Table 1. Table 1

Factors Responses

P _c C _m CS-C CS-P CS-S

(MPa) (%w/w) ER DT (s) ^~ ER DT (s) ER DT (s)00 (-1) 80 (+1) 0.76 380 1.02 530 1.77 15800 (-1) 40 (-1) 0.31 8 0.15 17 0.44 240 (+1) 80 (+1) 2.62 600 6.16 900 18.33 36040 (+1) 40 (-1) 0.71 15 0.26 30 0.99 5 120 (0) 40 (-1) 0.54 13 0.2 25 0.73 400 (-1) 60 (0) 0.36 12 0.36 23 0.61 9 120 (0) 80 (+1) 1.71 420 2.14 697 3.46 27040 (+1) 80 (+1) 0.82 25 0.8 45 1.56 20 120 (0) 60 (0) 0.58 18 0.53 35 1.07 15 120 (0) 60 (0) 0.6 20 0.52 34 1.02 10 120 (0) 60 (0) 0.57 18 0.55 37 1 20 120 (0) 60 (0) 0.57 18 0.51 35 1.05 15 120 (0) 60 (0) 0.56 17 0.53 35 1.02 15

120 (0) 60 (0) 0.62 20 0.54 36 1.01 20

In Table 1 , P _c represents compression pressure, C _sa represents salt concentration, ER represents elastic ratio, DT represents disintegration time (measured in seconds), CS-C represents CS carbonate, CS-P represents CS phosphate, and CS-S represents CS sulfate.

Example 3

Characterization of the optimal cross-linked CS with salts

[055] Throughout this Example 3, reference will be made to FIGS. 3-8D.

Fourier Transform Infrared (“FUR”) Spectroscopy

[056] An amount of about 5 mg of each CS salt, i.e. CS carbonate salt, CS phosphate salt, and CS sulfate salt, was mixed with about 250 mg KBr and scanned via“FTIR” (e.g., utilizing a IR Prestige 21, commercially available from Shimadzu, Japan) in a range between about 4000 cm ¹ and about 400 cm ¹ using 40 scans with a resolution of 2 cm ¹ .

[057] FIG. 3 illustrates a comparison of Fourier-transform infrared spectroscopy (“FTIR”) plots of CS salts prepared in accordance with embodiments of the present disclosure, wherein“CS-S” represents CS sulfate salt,“CS-C” represents CS carbonate salt,“CS-P” represents CS phosphate salt, and“CS” represents CS. More specifically, FIG. 3 shows“FTIR” spectrum plots of CS HC1 with absorption peaks at 1656 and 1595 cm ¹ , where these peaks may be attributed to the stretching of carbonyl groups of the secondary amides and the NH bending vibrations of the deacetylated primary amine (-NH2), respectively. Furthermore, the absorptions at 1124 cm ¹ and 1163 cm ¹ may indicate C-0 stretching, which are associated with the C6-OH primary alcohol and the C3-OH secondary alcohol, respectively. Upon the addition of divalent and trivalent anions to the positively charged CS HC1, it was observed that the carbonyl band (1656 cm ¹ ) and the amine band (1595 cm ¹ ) were shifted to lower wave numbers. This may indicate the formation of an ionic complex at the amino groups of CS HC1. The lowest changes were observed for CS carbonate salt, which may indicate the lowest interactions among other anions. The type of interactions developed may be ion dipole and electrostatic interactions as shown in FIG. 1. The functional groups of amine, carbonyl, and hydroxyl are considered as active sites in the CS HC1 structure that most likely interacted with the anions leading to dimensioning and/or shifting of the peaks of the active sites. Such changes could suggest the formation of an electrostatic complex.

Differential scanning calorimeter (“DSC”! and Thermogravimetric analysis (“TGA”)

[058] About 15 mg of each CS salt, i.e. CS carbonate salt, CS phosphate salt, and CS sulfate salt, was placed in a DSC cup and scanned using a previously calibrated simultaneous thermal analyzer (“STA”) DSC (STA 449 FI Jupiter ^® commercially available from NETZSCH, Germany). The heating rate was about 10°C/minute.

[059] FIG. 4 shows DSC thermograms of CS HC1, CS carbonate salt, CS phosphate salt, and CS sulfate salt. More specifically, FIG. 4 illustrates a comparison of differential scanning calorimetry (“DSC”) plots of CS, CS sulfate salt, CS carbonate salt, and CS phosphate salt, wherein“CS-S” represents CS sulfate salt,“CS-C” represents CS carbonate salt,“CS-P” represents CS phosphate salt, and“CS-H” represents CS HC1. The thermograms indicate the difference in decomposition temperatures. The onset of degradation of CS HC1 was at about 220°C. CS HC1 has the lowest thermal decomposition temperature compared to other CS salts, i.e. CS carbonate salt, CS phosphate salt, and CS sulfate salt. This may be attributed to crosslinking of CS with such anions, which made the CS backbone stronger and more resistant to thermal degradation. Crosslinking may increase the bonding and therefore increase the energy required to degrade the CS polymeric structure as depicted by the higher degradation temperatures for the three CS salts, i.e. CS carbonate salt, CS phosphate salt, and CS sulfate salt. The lowest degradation temperature was noticed for the CS carbonate salt, which could suggest it possesses the weakest interactions among the three CS salts, i.e. CS carbonate salt, CS phosphate salt, and CS sulfate salt.

Scanning electron microscopy (“SEM”) [060] Particles of the CS salts, i.e. CS carbonate salt, CS phosphate salt, and CS sulfate salt were mounted on aluminum stubs and then coated with gold by sputtering at 1,200 V, 20 mA, for 105 seconds using a vacuum coater. The surface morphology was then observed under an SEM (FEI Quanta 200 3D SEM, commercially available from FEI, Netherlands).

[061] The morphological differences were obvious. As shown in FIG. 5A, the CS HC1 showed thin flat filamentous structures with little pores, which may be attributed to its linear polymer structure with a high degree of flexibility at the molecular level. As shown in FIGS. 5B-5D, the CS anionic salts , i.e. CS carbonate salt, CS phosphate salt, and CS sulfate salt were more porous and aggregated, which may be explained by the formed cross-linked polymer strands, which could result in significant changes in ordering and arrangements of the CS polymer at the molecular level, which could be reflected as more condensed and porous particulate structures.

Flowabilitv test (using Carr’s Index (“Cl”) and Hausner Ratio (“HR”]]

[062] Bulk density is the weight of loose powder bed divided by its volume in a graduated cylinder. However, when exposed to mechanical stress due to tapping, the powder bed will shrink and the estimated density is called tapped density.

[063] Bulk and tap densities are used to describe the powder characteristic behavior mainly its flow properties. Also, these parameters were applied by certain equations (i.e. Hausner ratio; HR and Carr’s index; Cl) to determine powder flowability.

[064] Powder flowability is an important parameter to pharmaceutical industry in humidifying the powders of CS salts the powder bed will shrink and the estimated density is called tapped density compression m manufacturing of tablets. Powder flowability is used to describe the ability of a powder to fill properly a die in a compression machine.

[065] The bulk and tap densities were determined using a TAP-25 tapped tester (commercially available from Logan Instrument Corp., U.S.A.).

[066] Flowability of CS anionic salts can be determined based on HR and Cl according to the following relations

Ptap Pbulk

Cl = x lOO

V Pbulk ) wherein p _bulk and p _t represent bulk and tap densities, respectively.

[067] Table 2 shows flowability based on HR and Cl. Additions of divalent and trivalent salts to CS were found to decrease Cl leading to some improvements in CS flowability. This could be assigned to the crosslinking of CS with the divalent and trivalent anions, i.e. carbonate, phosphate, and sulphate.

Table 2

Material LOD Bulk Tap True Hausner Compressibility Powder

(%) density density density Ratio flowability

Index (%)

(g/cm ³ )

(n=l) (g/cm ³ ) (g/cm ³ )

(n=3)

(n=3)

CS-H 0.92 0.17 0.21 1.7804 1.2 19.05 FAIR

CS-C 0.85 0.44 0.53 1.7041 1.2 16.98 FAIR

CS-S 0.58 0.56 0.68 1.7423 1.21 17.65 FAIR

CS-P 0.67 0.6 0.67 1.7397 1.12 10.45 GOOD

Wherein“CS-H” represents CS HC1,“CS-C” represents CS carbonate,“CS-S” represents CS sulfate, and“CS-P” represents CS phosphate;

“n” represents the number of repetitions made in respect of an experiment; “LOD” represents Loss On Drying which is a test used to measure moisture content of a powder; and

True density is the actual density of the powder. True density estimates the solid fraction only without taking into account the intra- or inter- pores or voids in the powder bed. It is usually measured by special apparatus called Helium Pycnometer.

[068] As indicated in Tables 1 and 2, the crosslinking reaction resulted in excellent disintegration activity, good flow, and optimal tableting properties.

Moisture uptake

[069] Three samples of each of the CS salts powder i.e. CS carbonate salt, CS phosphate salt, and CS sulfate salt CS anionic salt samples, each of 1 g, were placed in Petri dishes and exposed to 33%, 75%, and 90% relative humidity desiccators at room temperature till equilibrium, i.e., till no change in powder bed weight (equilibrium is achieved after about 48 hours). The percent increase in weight of powder bed of CS salts was used to indicate moisture uptake.

[070] FIG. 7 illustrates a column chart comparing moisture uptake of CS salts prepared in accordance with embodiments of the present disclosure at different relative humidity levels, wherein“CS” represents CS,“CS-S” represents CS sulfate salt,“CS-C” represents CS carbonate salt, and“CS-P” represents CS phosphate salt. As depicted in FIG. 6, CS carbonate salt, CS phosphate salt, and CS sulfate salt showed higher moisture uptake compared to CS.

Water sorption ratio

[071] Three samples of each of the CS salts, i.e. CS carbonate salt, CS phosphate salt, and CS sulfate salt, each of 1 g, were placed in Petri dishes and exposed to 33%, 75%, and 90% relative humidity desiccators at room temperature till equilibrium, i.e. till no change in powder bed weight (equilibrium is achieved after about 48 hours). Then, three filter papers were placed inside each Petri dish and 10 mL distilled water was inserted. CS carbonate salt, CS phosphate salt, and CS sulfate salt, each weighing 0.5 g, were compressed at a pressure of 140 MPa pressure. The produced tablets were placed in the middle of the Petri dish and allowed to absorb water by the aid of the wet filter papers. The water sorption ratio (“WSR”) was calculated according to the following formula: M ₂ -M,

WSR

M ₁

Wherein M _l and M ₂ represents weight of compact before and after water sorption, respectively.

[072] WSR of tablets made of CS HC1 and CS anionic salts are illustrated in FIG. 7. FIG. 7 illustrates a column chart comparing water sorption ratios of CS carbonate salt, CS phosphate salt, and CS sulfate salt prepared in accordance with embodiments of the present disclosure after exposure to water for 5 minutes, wherein“CS” represents CS,“CS-C” represents CS carbonate salt,“CS-P” represents CS phosphate salt, and“CS-S” represents CS sulfate salt. As indicated, the CS HC1 tablet absorbed water and swelled; however it did not swell to the same extent as the CS carbonate salt, CS phosphate salt, and CS sulfate salt tablets. CS carbonate salt, CS phosphate salt, and CS sulfate salt formed cross-linked polymer systems, which enhanced water uptake and swelling tendency.

In vitro Dissolution test

[073] Ibuprofen lysinate, as an active pharmaceutical ingredient was selected as a drug model to test its dissolution behavior in a tablet containing one of the three CS salts, i.e. CS carbonate salt, CS phosphate salt, and CS sulfate salt A 3:2 weight/weight ratio of CS salts to ibuprofen lysinate was selected. About 500 mg of the mixture was compressed using a 15 mm circular die at a pressure of about 140 MPa. The prepared tablets were exposed to a dissolution test (UDT-804 dissolution tester, commercially available from Logan Instruments Corporation, U.S.A.) based on United States Pharmacopia version 29 (“USP 29”) ibuprofen tablet dissolution test. The dissolution conditions included using a USP phosphate buffer pH 7.2 (900 mL) as a dissolution medium, a paddle apparatus operated at about a 50 rpm stirring speed, and at a temperature of about 37±0.5°C. The samples were analyzed using an ultra-violet spectrophotometer (model no. UV-1800, commercially available from Shimadzu, Japan).

[074] FIGS. 8A-8D illustrate the dissolution patterns of the Ibuprofen lysinate in the tablets containing the different CS anionic salts, i.e. CS carbonate salt, CS phosphate salt, and CS sulfate salt. More specifically, FIG. 8A illustrates a plot comparing Ibuprofen lysinate release behavior obtained experimentally versus a predicted behavior when used with CS in accordance with embodiments of the present invention, wherein “EXP” represents experimentally obtained behavior, and wherein “PRED” represents predicted behavior. FIG. 8B illustrates a plot comparing Ibuprofen lysinate release behavior obtained experimentally versus a predicted behavior when used with CS carbonate salt prepared in accordance with embodiments of the present invention, wherein“EXP” represents experimentally obtained behavior, and wherein “PRED” represents predicted behavior. FIG. 8C illustrates a plot comparing Ibuprofen lysinate release behavior obtained experimentally versus a predicted behavior when used with CS sulfate salt prepared in accordance with embodiments of the present invention, wherein“EXP” represents experimentally obtained behavior, and wherein“PRED” represents predicted behavior. FIG. 8D illustrates a plot comparing Ibuprofen lysinate release behavior obtained experimentally versus a predicted behavior when used with CS phosphate salt prepared in accordance with embodiments of the present invention, wherein“EXP” represents experimentally obtained behavior, and wherein “PRED” represents predicted behavior.

[075] As depicted in the FIG. 8 A, the dissolution indicated a linear slow release of the ibuprofen lysinate from the CS HC1 tablet. However, as shown in FIGS. 8B-8D, rapid dissolution of the ibuprofen lysinate was observed for the tablets containing the other CS anionic salts. The mechanism of drug release was studied through curve fitting simulations using equations used that describe complicated release, where erosion, diffusion, and chemical binding are the factors affecting the release behavior. Table 3 shows the least squares of residues of different models used to describe Ibuprofen lysinate release out of CS salt matrix systems.

Table 3

Item Hopfenberg Gomperz Logestic Katzhendler Hill Weibull

CS-H 2.80* 8.76 24.10 37.38 9.20 8.02 cs-c 84.93 217.09 267.87 1004.80 18.82* 188.80

CS-S 80.83 237.11 299.93 857.62 25.14* 179.80 CS-P 73.18 197.48 225.08 909.65 15.37* 119.59

* lowest values were selected wherein CS-H represents CS HC1, CS-C represents CS carbonate, CS-S represents CS sulfate, and CS-P represents CS phosphate.

[076] The results in Table 3 indicate that Ibuprofen lysinate release was described in two different models. The release of ibuprofen lysinate was best described using Hopfenberg model for CS-H matrix, while for other CS anionic salts the best model was described by Hill’s equation.

[077] Table 4 shows model independent parameters.

Table 4

Model DE MDT (min)

Independent

CS-H 0.54 20.5

CS-C 0.85 6.9

CS-S 0.82 7.73

CS-P 0.81 8.52

wherein DE represents dissolution efficiency, MDT represents mean dissolution time, CS-H represents CS HC1, CS-C represents CS carbonate, CS-S represents CS sulfate, and CS-P represents CS phosphate.

[078] As shown in Table 4, MDT was 20.5 minutes for CS HC1 compared to 6.9-8.52 minutes for the CS salts, i.e. CS carbonate salt, CS phosphate salt, and CS sulfate salt. The DE was 0.54 for CS HC1 compared to greater than 0.8 for the CS salts. These results indicated a higher drug release behavior for cross-linked CS salts even to the most challenging negatively charged model molecule. Thus, CS salts could exhibit lower tendency to make electrostatic interactions with reactive molecules such as Ibuprofen lysinate compared to CS HC1.

[079] While embodiments of the present disclosure have been described in detail and with reference to specific embodiments thereof, it will apparent to one skilled in the art that various additions, omissions, and modifications can be made without departing from the spirit and scope thereof.

[080] In describing and claiming the present invention, the following terminology will be used.

[081] The singular forms“a,”“an,” and“the” include plural referents unless the context clearly dictates otherwise.

[082] As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a defacto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.

[083] Concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a numerical range of approximately 1 to approximately 4.5 should be interpreted to include not only the explicitly recited limits of 1 to approximately 4.5, but also to include individual numerals such as 2, 3, 4, and sub-ranges such as 1 to 3, 2 to 4, etc. The same principle applies to ranges reciting only one numerical value, such as“less than approximately 4.5,” which should be interpreted to include all of the above-recited values and ranges. Further, such an interpretation should apply regardless of the breadth of the range or the characteristic being described. [084] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the presently disclosed subject matter belongs. Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the presently disclosed subject matter, representative methods, devices, and materials are now described.

[085] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term“about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter.

[086] As used herein, the term“about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.

[087] As used herein, the term“and/or” when used in the context of a listing of entities, refers to the entities being present singly or in combination. Thus, for example, the phrase“A, B, C, and/or D” includes A, B, C, and D individually, but also includes any and all combinations and subcombinations of A, B, C, and D.