1.1 Introduction

In recent decades the general rate of population all over the world start aging. Ageing results from development of medical care and the ability to prevent fatal disease by imposing vaccination and evolve of medications which have capabilities to eliminate many types of illness and also enhance the quality of life. These factors lead to decreasing mortality particularly in developed countries, declining fertility rate may also play an important role in ageing propagation through communities which leads to reduction in proportion of children and increase older persons in population (Grant, et al, 2004). The World Population Aging Report (United Nations, 2013) observes that the global rate of older people between 60 years of age or over increased from 9.2% in 1990 to 11.7% in 2013 and will continue to rise and could be reaching 21.1% by 2050. In this context, chronic and complicated diseases predominantly associated with advancing age, a considerable proportion of elderly people principally over sixty years old suffering from disability, mental disorders such as Alzheimer or psychotic disease, forgetfulness,  the problem is compounded especially if they are on multiple types of medications, risks such as repeating, missing, and incompliant of medications dose might affect their life quality and health which subsequently  lead to depression  and even death (Suh, et al, 2009),  a sustain release drugs could  be useful solution for those type of patient, Sustain release drug delivery system can be identified as a regulation of drug delivery that assist  slower or steadier releasing of a single dose over a period of time which prolong the therapeutic effect, decrease dose frequency and detraction of peak fluctuation for blood concentration  which reduce possible side effects enhance drug bioavailability and could also improves drug distribution (figure 1), the advantages of this technique for elderly patients is significant relating to decrease the number of doses, avoid night doses which improve patient compliance and provide a better control of the disease status, additionally it might increase safety by reduce fast absorption of high potency drugs in the plasma level therefore maximise utilization of the single dose, reduce health costs , and supply better control of drug absorption rather than the conventional immediate release tablet (Dixit, et al, 2013)

In contrast, Pradesh, District (2013) point out that if there is a toxic substance within sustain release formulations it will stay in the body after administration for a long period of time, and then the body will take a long time to completely eliminate the toxic material and that’s lead to difficulty in titrating patients and inflexible dose scheduling.

 

 

Figure 1: Drug release from sustained release delivery system. Here drug substance is coated by a release control polymer (either a natural resin or a synthetic polymer).

 

 

 

In addition, recent surveys have shown that many elderly patients are suffering from dysphagia or difficulty of swallowing, in principle, the oral route is the favourable way for drug administration, hence swallowing difficulties is considered as substantial obstacle and a major challenge for safety and efficacy of medicine especially when elderly patients intend to administer their medications by oral route.

Kelly et al. (2009) indicated that 35-68% of older people had difficulty of swallowing, and it is not solely complicate digesting of food process and drinks fluid but it also includes swallowing of oral medications. A survey of 477 patients in England who had dysphagia reveals that 68% (n= 324) were trying to open capsules, crush the tablets, or even mix the powder with drinks or food for being easier to swallow, problems like carcinogenesis it seems to be occurred when patients did that with anticancer drugs, in addition such process would delay or accelerate the absorption rate of drugs which could lead to severe side effects due to drug overdose and toxicity or delay the appropriate absorbing rate of that’s type of dosage form then prolonged the illness symptoms, moreover degradation of the active ingredients of enteric coating tablets like omeprazole in a stomach its result from destroying the protective layer of tablet and many kinds of antibiotic, and then being inactive after exposing to the stomach acids, therefore this method  prevent those tablets from exert their actions after they will absorbed from intestine (Mitchell J, 2008), were 64% (n=305) of them refused taking their oral drugs when prescribed due to they had dysphagia.

A significant harm particularly occurred with modified release formulations due to they usually contain larger dose than the conventional release tablets. Crushing tablets or opening capsules is prohibited with modified release formulations because such process can disrupt the releasing profile of the drug and produce drug overdose which lead to toxicity. The problem can be primarily solved by the physicians or the pharmacist by omitting any unnecessary medication or prescribing a combinational drug which has more than one active ingredient in one drug dose, and finding an alternative pharmaceutical dosage form such as, sublingual, Buccal tablets, suppositories, inhalations, transdermal, or another medicine with comparable pharmacological effect would be prescribed, for instance, transdermal glyceryl trinitrate patches instead of modified-release isosorbide trinitrate, however the problem might manifest  if there is no pharmaceutical dosage form replacement then the patient will find himself compelled to accept oral medication (Kelly et al. 2009)

In this perspective, a convenient sustain release drugs for dysphagic patients getting a profound importance in last years, many pharmaceutical industries were trying to overcome these hassles.

 

-Approaches to ease drug administration of sustain release formulations for patients with dysphagia:

Ionic exchange resin:

Hirsh et al. (2004) pointed out that a progression has been made for sustain release drug formulation in context of facilitate swallowing. The drug composition can be complex with ion exchange resin to form a tiny multi particulate less than 150 microns, the drug-resin complex resulted from binding with the salt form of the drug, at that point the resin can coat the active ingredient of the drug to prompt modified release property. The coating materials comprise of an aqueous dispersion of a synthetic polymer for example: poly (ethylacrylate  methylmethacrylate-triethylammonioethylmethacrylate Chloride).  At that juncture these can be ultimately formulated into the ending dosage form like: gel, soft gelatine capsule, suspension, rapidly dissolving tablet chewable tablet, and sachet for reconstitution to create easier swallowing dosage form. Similarly, Ichikawa, et al. (2001) emphasize that using of drug ion exchange resin complex as a core particle has the ability to form 100 ?m- microcapsules sized and it can produce sustain release property, the drug can be loaded in anionic exchange resin then fractionated into 200–400 mesh and then microencapsulated with Eudragit® RS30D, in other embodiment, Cherukuri (2012) explains that rapid disintegrated controlled release tablet which is dissolve quickly in the mouth can be a substitute choice for paediatric or geriatric patients who have difficulty in swallowing and its effectiveness is similar to conventional capsules or tablets (Figure 2)

Figure 2. In vitro-drug release (cumulative percent drug release) of the Dextromethorphan HBr from the rapid melt controlled release tablets in1.2 pH followed by 6.8 pH phosphate buffer. (Cherukuri 2012)

 

Complexing of the drug active ingredient Dextromethorphan with resin can cover unpleasant flavour by adsorbing into ion exchange resin.  Strong acid cation resins (sulfonated styrene-divinyl benzene copolymer products) can mask basic drug’s unpleasant flavour while strong basic cation resin has the ability to cover acidic drug unpleasant flavour.

However, there is concerned with this technique such as poor compressibility due to the existence of resin. The coated particles of drug-resin composite agglomerate during compression which can be resolved by applying the lowest compression force, which also leads to an extended control release of the medication.

In situ gelling sustained release:

In situ gelling formulation intended for sustain release drug delivery is consider as a useful style for dysphagic patients. Itoh et al. (2011) clarify that gels formed by addition of pectin (0.5–2.0%) and methylcellulose (1.0–2.0%) with 20% d-sorbitol and calcium ions in compound improve the gel strength formulation and viscosity can stimulate comfort administration for dysphagic patients, then after administration the gel will formed in situ reserved their integrity in stomach for appropriate time for sustained release to be attained, Methylcellulose is a water soluble polysaccharide that can form a thermoreversible hydrogel in water by being heated at 55C?above and by adding sorbitol the temperature can be reduced to be more convenient to body temperature. Whereas pectin is anionic polysaccharide which could form hard gel when compounding it with calcium through ion responsive gelation. The combination can form thermo-ion responsive vehicle oral sustained drug delivery which is achieved in situ gelation and is more complimentary for dysphagia patients.

Likewise, Miyazaki et al. (2009) highlight that gel formulation encompasses of gelatin, agar, gallan, pectin, and xyloglucan and can produce oral sustained drug delivery system to dysphagic patients,

where Gellan (1.5% w/v) and xyloglucan gels (1.5% w/w) deliver ease of oral administration mostly as a liquid and then can be transformed to the gel in the acidic media as stomach to attain sustain release property. In situ gelation of gallen and pectin solution is prepared by complex nonionise calcium++ to release free Ca + ions when reached to acidic media in stomach and prompt immediate gelation which act as a vehicle for oral sustained drug delivery. Shimoyama et al. (2012) observe that patients with dysphagia capitalize from liquid dosage form using in situ gelling characteristics. A mixture of solution containing methylcellulose (2.0%) and sodium alginate (0.25–1.0%) with 20% d-sorbitol was accomplished comfort of administration as a liquid and it transformed to gel in the stomach to implement sustained release.

Microparticulate sustain release:

Yamada et al (2001) indicate that a microparticulate of ketoprofen (420–600 ?m) can be settled as sustained release. An increment of patient compliance is attained by decreasing dose frequency principally for those patients who are distressed from chronic diseases like rheumatoid arthritis or pain. The core of the micropariculate has ketoprofen as an active ingredient, Eudragit L100, and calcium salt to increase drug solubility.

While the covering material contains carboxymethylethylcellulose, and ethyl cellulose, which provides ketoprofen control release.

After primary prompt release, the microparticles deliver a constant plasma level, and can be existing as sustained release.

Xiao et al. (2015) reveals that curcumin anti-inflammatory drug loaded microparticles can perform as sustain release drugs for ulcerative colitis where the manufacture of microparticles has been prepared by the emulsion solvent evaporating method with modified pH sensitive Eudragit (S100), poly lactide-co-glycolic acid (PLGA) and microparticles were loaded with curcumin to yield 1.52 to 1.91 ?m particle size. The existence of (PLGA) can reduce curcumin release from microparticles to show sustain release orally administrated which is reflect valuable ulcerative colitis cure.

Correspondingly, Mittal et al. (2007) indicate that estradiol can be loaded in poly lactide-co-glycolic acid (PLGA) microparticle by the emulsion evaporation technique which can stimulate sustained release of the oral dosage form and improve bioavailability, whereas the release duration depend on particle size and molecular weight that increases when compact in size. Zhang et al. (2013) observe that diatoms which have porous silica based materials micropartilcles might load prednisone by the immersion process may supply sustained release formulation as well as offer safety of administration which is optimize patient compliance, and develops permeability.

Jelly and gel formulations:

Miyazaki, et al. (2009) state that gel formulations for oral administration is getting preference for dysphagic patients, Paracetamol can be loaded within these formulation with a proper rheological characteristics to achieve ease of swallowing, whereas the ability of gel to maintain their integrity in the acidic environment such in stomach enabling sustain release feature. The gel contain gelatine, gellen gum, pectin, agar, xyloglucan can provide a sufficient gel strength to exert prospective sustain release property. Similarly, Miyazaki, (2011) entailed that using of i –carrageenan for gel formulation provide better gel strength than agar gel, thus i –carrageenan has superior sustain release feature, and their viscosity is convenient to use as vehicles for oral delivery of medications to patients suffering from difficulty of swallowing. Moreover Prakash, et al. (2014) agree that medicated jelly formulations are useful and convenient for patients suffering from difficulty of swallowing, although with presence of various dosage form such as: suspension, chewable tablet, solution, powder for reconstitution, many disadvantages occurred with them like: improper measurement, stability, dose waste, ease of administration especially if those patients administered syrup or suspension which may chocked them, this problem can be solved by using a thickening material to increase solution viscosity or using jelly formulation, jelly prepared from gellan gum, pectin, pectin-guar gum can be act as a drug vehicle for carbamazepine and could enhance their solubility, in addition to enhance dysphagic patients acceptability,

Satyanarayana, and Keshavarao. (2014) reveal that gels prepared by natural polymer like silk fibroin with a proper rheological properties can act as a salbutamol sulphate vehicle and it offer ease of administration for dysphagic patients, using of Fourier transform infrared spectroscopy and Differential scanning calorimeter (DSC) detect that the drug is biocompatible with their gel vehicle, while in vitro release show that the formulation are able to sustain drug their release up to 90 minutes.

1.3 Aim and objective

the aim of this project is to perform an ideal jelly, investigate the property of each contributed material used in formulation and realize the correlation and interaction between them, in addition to the impact of those factors into the final formulation, in this context, former characterization assessment would be done by observe the visual appearance of those preparation for instance: assess visually if thickened fluid flow when invert their container, in contrast gel has to be not flowing when container is inverted, and whether if jelly formed a standing gel and if its hold their shape when cut by spatula and whether it quivers or wobbles in order to be easy for swallowing, and consider their colour and homogeneity, thereafter, evaluating if the vehicles are heterogeneous by present of swollen granules by using light microscopy, and ultimately testing the texture and rheology of the formulation by using texture analyser and rheometer instrument.

In essence such formulations can act as a drug vehicle where the active ingredient of the drug can be loaded into them with the ability to control drug release, in order to facilitate their administration by oral route principally for those patients suffering from dysphagia, further testing would be prepared to ascertained that these formulation attain their purpose, in vitro experiment by using an artificial throat can be testify whether that’s formulation passing smoothly through the throat or not (Weel, et al. 2004), The influence of the mixture on the drug properties such as drug content, and drug release, plasma concentration, and correlation between in vitro and in vivo release have to be examined (Yamada et al, 2001).

2. Materials and methods:

2.1 Materials: Different types of sodium alginate: (1740, 5450, 8223), Pectin, iota carrageenan, lamda carrageenan, Kappa carrageenan, Xanthan gum, Low acyl gellan gum, High acyl gellan gum, Gum Arabic, Gum Karaya, Gum tracaganth, Guar gum, Locust bean gum, Pregelatinised corn starch, Precooked acetylated di-starch phosphate (from potato), Precooked acetylated di-starch adipate (Waxy maize), Polyethylene oxide, Carbopol, HPMC s, Egg protein, Cekol 2000, Hartley’s readymade jelly, Hartley’s jelly powder.

Additional material needed for the test such as: Calcium chloride, calcium sulphate, calcium carbonate, Sucrose, Citric acid, Disodium hydrogen phosphate, Potassium dihydrogen phosphate, Tween 80, Potassium chloride, Sodium chloride, Maltodextrin, Glycerine, acetone, oasis summer fruit drink, Deionised water was used for all the experiments.

2.2 Methods:

Commercial brand jelly:

A commercial brand ready-made jelly prepared by heating process called Hartley’s contained: water, sugar, fructose syrup, gelling agents such as: locust bean gum, Xanthan gum, gellan gum, citric acid, has been brought to the lab to assess their characterization by using of different criteria such as: rheometer, and texture analyser, afterward consider the former jelly characterization as an ideal jelly to compare their properties to another jelly formulations prepared in the lab in order to enhance their properties.

Furthermore, another commercial brand jelly powder belong to the same company (Hartley’s) was obtained to prepare in the lab, the sachet content was poured into 500 mL beaker, while 300 mL of deionised water was heating in another beaker on hot plate to 100 C?, after that the boiling water has been added to the beaker which contained that powder and magnetic stirrer, the beaker placed on stirring machine with 180 rpm speed to let the powder dissolve, then 200 mL of oasis summer fruit drink was added to the beaker for stirring until it thoroughly mixed through the solution, the solution was placed in fridge to form jelly.

Similarly, the previous jelly formulation undergone to the same characterization assessment criteria to identify their properties.

Lab prepared Jelly:

Posteriorly, different jelly preparation was performed in the lab by using two techniques, the first approach follow the traditional way of making jelly through applying heat during mixing gelling materials, 0.5% of Kappa carrageenan (100 mg) and 0.33% of locust bean gum (66 mg) were weighed by using weighing machine EP213, then poured to 100 mL beaker containing 20 mL of deionised water and magnetic stirrer placed on hot plate with 100 C?, the stirring with heating process operating till powder dissolved, after that the beaker transferred to the fridge to form jelly.

while the second technique used sodium alginate and calcium chloride, the privilege of this technique over the preceding one it’s the ability to form jelly in a short period of time, the jelly formed by dispersing sodium alginate (200 mg) in 10 mL of deionised water by using 100 mL beaker containing magnetic stirrer, and disperse calcium chloride in another 100 mL beaker containing 10 mL of deionised water and magnetic stirrer placed on multi-channel stirrer MS-52M with 180 rpm speed, once powder hydration occurred, calcium chloride solution was added into sodium alginate solution to form jelly.

Measuring sodium alginate hydration time by using stop watch is important to decide which sodium alginate type is dissolve faster in water.

Gelling material hydration time test:

1% (200 gm) of gelling material include: HM Pectin, LM pectin, iota carrageenan, lamda carrageenan, Kappa carrageenan, Xanthan gum, Low acyl gellan gum, High acyl gellan gum, Gum Arabic, Gum Karaya, Gum tracaganth, Guar gum, Locust bean gum, Pregelatinised corn starch, Precooked acetylated di-starch phosphate (from potato), Precooked acetylated di-starch adipate (Waxy maize), Polyethylene oxide, Carbopol, HPMC s, Egg protein, Cekol 2000, were dispersed individually in 100 mL beaker containing 20 mL of deionised water and magnetic stirrer, the hydration time of each material was recorded by using stop watch, other characteristic such as: formed material, visual appearance was observed, thereafter, the process was repeated by adding (1% of sucrose, 2% of sucrose, calcium sulphate, calcium chloride, calcium carbonate,  maltodextrin, tween 80, glycerol) to each material, the hydration time after the additive factor was recorded to find out whether the hydration time improved or retard, essentially this experiment can identify the formed material of each substance in water, and determine their hydration time in order to perform an instant jelly.

Jelly Development experiment:

This experiment intend to develop an instant jelly formulation characteristics  by testing different methods, then figure out which jelly characteristic is much appropriate:

1. as a first method the ratio between sodium alginate and calcium chloride remain constant (1:1%) for addition of 1% of other gelling material, the additional gelling material was added first to the beaker containing 1% of sodium alginate and 10 mL of deionised water, while the opposite beaker contained 1% of calcium chloride dispersed in 10 mL of deionised water, after powder hydration occurred, calcium chloride solution was added to the former beaker to form jelly.
2. Then as a second method 1% of the additional gelling material was added to 100 mL beaker contained 1% of calcium chloride and 10 mL of deionised water, while the opposite beaker contained 1% of Na alginate and 10 mL of deionised water, thereafter similarly, calcium chloride and new material solution was added to Na alginate beaker to form jelly, the difference such hydration time and visual appearance of each formulation was observed.
3. After that, another technique was processed in the lab to entail jelly development exploration procedure, a 75% = (1.5%) of sodium alginate verses 25% = (0.5%) of additional gelling material powder were mixed together then dispersed in 10 mL of deionised water, while the opposite beaker contained 1% of calcium chloride dispersed in 10 mL of deionised water, once the powder dissolved calcium chloride solution was added to the opposite beaker to form jelly.
4. Thereafter, as a fourth method 25% = (0.5%) of sodium alginate verses 75% = (1.5%) of additional gelling material powder were mixed together then dispersed in 10 mL of deionised water, while the opposite beaker contained 1% of calcium chloride dispersed in 10 mL of deionised water, once the powder dissolved calcium chloride solution was added to the opposite beaker, the hydration rate and the visual appearance for each mixture was observed for selection of the best jelly features.

After that the best jelly features figured out, the formulation process repeated again to assess their characterisation by using different criteria such as: the hydration time, weigh of formed jelly, water remained, visual appearance, the best two characteristics of them were obtained to determine their properties by using rheometer and texture analyser instrument, then compare their result with the commercial jelly result.

Rheometer test:

Steel plate (40 mm) was used for TA instruments AR1500ex Rheometer + Julabo AWC100 cooling system, nitrogen gas pressure gauge was turn into 20 Bar, Rheometer, Julabo, and computer was turn on, then rheology advantage application was used to measure the rheology of the samples, calibration was done to the intending force applying to the sample through option- instrument- calibration- calibrate inertia, then rotational mapping was prepared by press on the left, 5mm gap was selected from left zero gap icon, while 650 mm gap to calibrate the back-up, the stress step test was used firstly with 25 C? temperature, from oscillation process 0.1- 1000 torque and frequency 1 were chosen, direct your result to your file from choosing result destination in order to save it, thereafter suitable sample portion was transferred underneath the spindle force, then the spindle was moved down to the adjusted gap by pressing on left icon, after that bearing lock button was pressed to remove the sample waste from the edge of the plate, after that the test was run by pressing on the green upper left button, the response of the sample was recorded by the rheometer by applying various force, once the test finished, the remaining sample was removed and the spindle was cleaned for doing frequency sweep test, to prevent destroying the next sample the strain % was adjusted to 0.0300 from ? left icon, frequency sweep test was chosen from oscillation procedure and the same procedures were done to figure out the test result, after that steady state flow test was accomplished by following the same procedures.

Texture analyser test:

41765 TA-XT plus texture analyser was used for this experiment, the test was prepared by using exponent software, Jellies and films was chosen as a product type from Help and education zone, then determination of bloom strength button was pressed, the spindle was moved down to penetrate the sample surface by press on TA- Run to measure the force, the distance, the time, the maximum force to penetrate the sample is determined by bloom strength, while the adhesion is measured when the spindle moved up to determine how sticky the sample is, the test was done triplicate to different site on the sample surface, and the sample results were saved.

 

 

3. Results:

Preparation of Jelly by dispersing 1.5% of sodium alginate 1740 in 10 mL of deionised water and calcium chloride dispersed in another beaker contained 10 mL of deionised water and then mixing both together by adding CaCl solution to sodium alginate beaker.

 

The experiment reveals that using of 1.5% of sodium alginate 5450 takes more than one hour to disperse in 10 mL of water, as well as sodium alginate 8223 which takes more than 40 min, for that reason sodium alginate 1740 type has been chosen for all this experiment steps, moreover the weight of jelly formed decrease with increase of CaCl concentration, while an increment in water remain volume occurred with CaCl concentration raise, correspondingly with an increment of performed jelly cohesiveness.

Experiment No.	Content concentrations with adding 10 mL of deionised water for both of them	Na alginate 1740 hydration time	Weigh of jelly formed	Water remain	Visual characteristics	Visual appearance
1	Na alginate 1.5% Ca Cl 0.3%	7:30 min	16.806 gm	0.5 mL	Standard gel, transparent, quivers, light	Not uniform, not cohesive
2	Na alginate 1.5% Ca Cl 0.5%	9 min	13.561 gm	4.3 mL	Standard gel, transparent, hold it shape, tough	Not uniform, not cohesive
3	Na alginate 1.5% Ca Cl 1%	7:30 min	10.919 gm	6.20 mL	Standard gel, transparent, hold it shape, tough	Uniform, cohesive
4	Na alginate 1.5% Ca Cl 1.5%	7 min	12.142 gm	6.60 mL	Standard gel, transparent, hold it shape, tough	Uniform, cohesive
5	Na alginate 1.5% Ca Cl 2%	4:30 min	11.516 gm	6.80 mL	Standard gel, transparent, hold it shape, tough	Uniform, cohesive
6	Na alginate 1.5% Ca Cl 2.5%	6:30 min	11.620 gm	7.20 mL	Standard gel, transparent, hold it shape, tough	Uniform, cohesive
7	Na alginate 1.5% Ca Cl 5%	7 min	11.103 gm	7.80 mL	Standard gel, transparent, hold it shape, tough	Uniform, cohesive
8	Na alginate 1.5% Ca Cl 10%	7 min	11.863 gm	8.20 mL	Standard gel, transparent, hold it shape, tough	Not uniform, smooth surface
9	Na alginate 1.5% Ca Cl 15%	7 min	11.476 gm	8.50 mL	Standard gel, transparent, hold it shape, tough	Uniform, smooth surface
10	Na alginate 1.5% Ca Cl 20%	6:30 min	9.146 gm	11 mL	Standard gel, transparent, hold it shape, tough	Uniform, smooth surface

Preparation of Jelly by dispersing 1.5% of sodium alginate 1740 in 15 mL of deionised water and calcium chloride dispersed in another beaker contained 5 mL of deionised water and mixing both together.

 

Experiment No.	Content concentrations with adding 15 mL of deionised water to Na alginate, 5 mL to Ca Cl	Na alginate 1740 hydration time	Weigh of jelly formed	Water remain	Visual characteristics	Visual appearance
1	Na alginate 1.5% Ca Cl 0.3%	7 min	9.747 gm	7 mL	Hard jelly, transparent, light, hold it shape	Not uniform, Not cohesive
2	Na alginate 1.5% Ca Cl 0.5%	3 min	15.160 gm	7 mL	Hard jelly, transparent, tough, hold it shape	Not uniform, Not cohesive
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