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Summary. Iontophoresis – is a method of utilizing a little electric charge to present a medical specialty or other chemical through the tegument. Iontophoresis nowadays is being used for either heightening the incursion of molecules, such as porphyrins, aminolevulinic acid [ 1, 2 ] through tegument or to cut down their permeableness ( such as Fentanyl ) [ 3 ] .

Objective. The purpose of the survey is to explicate an optimum pharmaceutical iontophoretic bringing signifier and to analyze the dependance of its quality and stableness on the polymer used for the formation of footing, the viscousness of the vehicle and its electrical conduction ( in due to the necessity of the molecules to be in an ionic province ) .

Materials and methods. For the preparation four polymers ( carbopol ( carbomer ) , methylcellulose, hypromellose and hydroxypropylcellulose ) have been selected. Besides potentiometry, conductometry and viscometry have been applied.

Consequences. In the hunt of optimum pharmaceutical signifier, different polymers and different concentrations ( 0.25 – 10 % ) have been tested. During experiments different viscousnesss have been obtained ( 1.5 – 10000 mPa/cm ) . Assorted pH values for the preparation have been applied but small or no correlativity has been noticed between the pH value and the viscousness.

Decision. The optimum pharmaceutical signifier for ionic medication is a gel readying of optimum viscousness ( 1000-5000 mPa/s ) and conduction. Refering the per centums of polymer in the readying the optimum option is 1 % of carbopol, 4 % of methylcellulose and 2 or 3 % of hypromellose. Conduction of the vehicle besides influences the ionic medication – in most instances lower viscousness induces higher conduction ( as the correlativities are rearward ) . The pH should change from 5 to 7.4 ( because the integrated substance must remain stable and skin must non be irritated ) [ 4 ] .

Introduction. For the bringing of anticancer drugs through tegument by ionic medication optimum pharmaceutical signifier is being designed. The chief purpose is to measure its oraganoleptic belongingss and the optimum viscosity/conductivity ratio for iontophoretic bringing.

First, four polymers matching to the chief factors of quality ( suitableness for gel preparations, lubrication and stableness ) [ 5, 6 ] have been chosen for the preparation of the vehicle. The chosen vehicles and their characteristics are listed below:

Carbopol ( carbomer ) – polymers of acrylic acerb cross-linked with polyalkenyl quintessences or divinyl ethanediol. They absorb H2O, acquire hydrated and swell. Carbomer has hydrophilic characteristics every bit good as its cross-linked construction and its unsolvability in H2O makes carbopol a possible campaigner for usage in controlled release drug bringing system [ 7, 8, 9 ] .

Methylcelullose – is a polymer of long-chain substituted cellulose in which 27 – 32 % of hydroxyl groups are in the signifier of methyl quintessence. It might be used for the formation of the gel footing, as a coating agent, emulsifying agent etc. [ 7, 8, 10 ]

Hypromellose – is a partially O-methylated and O- ( 2-hydroxypropylated ) cellulose. It is an odorless, tasteless, white or creamy white hempen or farinaceous fibre, used as an emulsifier, suspending agent or stabilizing agent for topical readyings [ 7, 8 ] .

Hydroxypropylcelullose – cellulose, 2-hydroxypropyl quintessence. It is a white to somewhat yellow -coloured, odorless and tasteless pulverization used as emulsifying, stabilising and suspending agent in semi-solid readyings [ 7, 8, 11 ] .

Two chief parametric quantities are examined for the preparation of optimum iontophoteric signifier – viscousness and conduction. Viscosity for this system should be 1000-5000 mPa/s ( 100-500 hertz ) . Conduction should be every bit high as possible for perforating molecule to travel every bit fast as it can through tegument until the impregnation of tegument pores [ 12 ] . The flux of the molecule correlates to the ionisation of the molecule and the vehicle. Besides for the preparation of gels such factors as warming and commixture is evaluated. For stableness the monitoring of pH and viscousness daily or week-to-week is being measured in carbopol gels. Evaluation of the quality and stableness parametric quantities should be relevant in the hereafter in the design of iontophoretic gel as a vehicle for incursion of anticancer drugs through tegument.

Materials and methods.

Chemicals. As the footing for gels carbopol 980 ( CP ) ( Lubrizol, USA ) has been purchased. Methylcellulose ( Metholose SM ) – Megahertz, hypromellose ( Metholose SH ) – HM and low substituted hydroxypropyl cellulose NF – LSHPC have been received from Shin-Etsu ( Japan ) as a gift. For accommodation of pH K hydrated oxide ( BDH Laboratory Supplies, England ) and hydrochloric acid ( Sigma-Aldrich, Germany ) have been used.

Equipment. SV Series Sine-wave Vibro Viscosimeter ( A & A ; D Company, Japan ) for mensurating viscousness and WTW InoLab series conductometer ( WTW Wissenschaftlich-Technische

Werkstatten GmbH, Germany ) for mensurating conduction have been used. Mixing has been performed by magnetic scaremonger MSC BASIC ( IMLAB bvba, Belgium ) .

Lab proving. The rating and accommodation of pH values, measuring of conduction and viscousness has been performed.

Consequences and Discussion

The showing of polymers for readying of iontophoretic gels, the influence of commixture and heating on their quality, choice of optimum concentration of polymers

After methanalysis of literature [ 10, 11, 13, 14, 15, 16, 17 ] four polymers have been selected for the preparation of footing for iontophoretic gel. One polymer – CP is of a polyacrylic nature, the other three – Megahertz, HM, LHPC – are cellulose derived functions.

First measure was the choice of optimum concentration of these polymers and extra steps ( if needed ) for preparation of the gel. Extra steps included heating up to 70oC and blending ( Table 1 ) .

Table 1

pH stableness through yearss

Normally, while fade outing different concentrations of polymer the pH value in all of them differs by less than 5 % as polymers themselfs eqate the acid/base balance. The pH value independently from concentration for every sort of polymer is about the same ( Fig. 1 ) .

Figure 1

The resuls show that before pH accommodation independendly to the concentration of the polymer the pH of the gels of same polymer are really similar ( RSD = A±10 % ) . As it is shown in Fig.1 CP gels hold avarage pH of 4.4, MC – 6.3, HM – 6.4. All are of acidic and it is more obvious in CP gel of acrylic beginning. Cellulose gels have higher pH.

The pH accommodation is being performed in the period of three yearss after the preparation. It depends on the clip required for the preparation to go stable and for the polymer to swell and fade out wholly in the H2O [ 18, 19 ] . After the adjustement, re-adjustment is performed after one twenty-four hours and so pH is measured about in the period of 1 month [ 20 ] .

Consequences of re-adjustment: in many instances the difference from intended pH significance is few decimals or none before re-adjustment. But in some instances they may differ even in 1 pH unit – that is why re-adjustment must be performed.

Consequences after re-evaluation of pH in one month: in many instances the existent pH value is the same as intended one – the differences vary from 0.1 to 0.3 points per figure. So the pH value after the re-adjustment is statistically stable plenty.

The influence of temperature on the stableness of carbopol gels

For the rating of opposition to temperature and the influence of temperature on the viscousness of carbopol gels few pH values which will most likely be used for the preparation of pharmaceutical signifier are selected. The pH values are chosen consequently to the ability to prolong the stableness of antineoplastic drug ( which will be incorporated into the formation ) and the non-irritability to the tegument [ 21 ] .

The consequences of this experiment have been shown in the image below ( Fig. 2 ) .

Figure 2

In general means the viscousness ( opposition ) should diminish while temperature additions but carbopol gels are complex polymer preparations and in the influence of temperature the construction reformulates itself. Therefore, the addition of viscousness in the presence of lifting temperature is enrolled ( Fig.2 ) .

Besides, it is rather obvious that gels which have been mixed have higher viscousness of about 15 – 20 % . The commixture increased the viscousness of CP gels ( pH=5 and pH=7 ) ) ( Fig. 2 ) .

The highest viscousness of non-mixed CP gels is of the pH=6 gel, but other gels are suited for ionic medication every bit long as they form the right vehicle and their viscousness is adequate.

The alteration in viscousness under the influence of temperatute ( it rises by 30 grades from 25oC to 55oC ) varies from 4 to 10 % . Normally, the gels while hive awaying do non make mentioned conditions, so it might be considered that the gels are stable transdermic signifiers in room temperature.

Viscosity survey

Viscosity is one of the chief factors act uponing the preparation of optimum semi-solid pharmaceutical transdermic drug bringing signifier [ 9, 22 ] . For ionic medication of hydrophylic molecules gels are chosen as optimum vehicles. Consequently to literature [ 9, 10, 15 ] , optimum scope of the per centum of polymer put into a gel preparation is exluded. As it is shown in Fig. 3 below MC has the highest viscousness characteristics, every bit good as CP has the lowest 1s. After this rating, optimum concentrations form the scopes are excluded ( CP – 1 % , HM – 2 and 3 % , MC – 4 % ) . These values are chosen as the viscousness is in the optimum scope or it becomes optimum after pH accommodation.

Figure 3

Sing the addiction of viscousness on the pH value the consequences are rather helter-skelter. The acid-base balance has different effects on gel readyings. The viscousness jumps up and down consequently to pH but the correlativity is non clear and additive. As an illustration, below you can see Fig.4 which represents the helter-skelter addiction of 1 % CP, 1 % HM and 3 % MC gels on their pH values. In this illustration, the viscousness for CP is increasing up to a value of pH=8 except one point ( pH=7 ) where it drops. For MC the viscousness dectrases until pH=6, so it increases up to pH = 7.4 and beads at pH=8. It is besides helter-skelter sing the HM curve. In other illustrations, the highest extremum of viscousness might be in the centre or the terminal of the pH values. Sing other concentrations or polymers the same regulations apply – there is no inclination on the increasment or decreasment of pH as polymers have a complex construction that is rather sensitive to pH alterations.

Figure 4

Conduction survey

Conductivity is particularly of import in ionic medication because the transit rate is straight connected to it [ 2, 23 ] . For the export to the tegument, the molecule of the drug must be ionized. In this instance we have non incorporated an active substance – the conductuvity has been measured for the gels as vehicles for ionic medication.

The correlativity between increasing per centum of polymer in the composing of the gel and conduction has been established as it is shown in Fig. 5. Besides, in comparing to Fig. 3, lower viscousness produces higher conduction.

Figure 5

It is noticed that in most instances lower viscousness is connected with higher conduction. Though the correlativity largely is non really strong. Correlation coefficients for different groups or polymers and their different concentrations vary: for HM the strongest correlativity is in the group of HM 1 % concentration ( -0,63 ) – medium correlativity, MC 1 % – adequately -0.69 ( medium ) , CP 0,5 % – ( -0.73 ) ( strong ) . In other instances the correlativity is largely weak and contrary.


As optimum pharmaceutical signifier for ionic medication must basically present the characteristics of optimum viscousness and conduction, foremost the stuffs for gel formation have been selected – these are CP, MC, HM, but non LHPC as it did non organize the gel. It has been evaluated that the pH of gels has an influence to its characteristics such as conduction and viscousness, though the correlativity might be weak. The correlativity between conduction and viscousness may be every bit good, though, in many instances it is rearward and weak. So, the creative activity of optimum vehicle for ionic medication depends on the substance that has to be incorportaed into the gel. Consequently to its characteristics the conduction, viscousness and the pH of the vehicle must be adjusted. In footings of quality and stableness manufactred gels are suited for incorporation of the drug and application for iontophoretic therapy.

Table 1. The selecton of optimum footing and extra steps for the preparation of gel. CP-carbopol ; MC – methylcellulose, HM – hypromellose. LHPC – low-subsituted hydroxypropylcellulose.


Optimum concentration ( harmonizing to viscousness ) *




0.5 and 1 % ( depending on pH the viscousness varies from 213 mPa/s to 9580 mPa/s ) are chosen for farther experiments

Heated H2O has non been used for the readying as it is non mentioned in the specification

Blending enhances the viscousness by 15 – 20 % though gels without blending are of a good quality, hence, blending will non be applied in farther inversigations.


3 % , 4 % and 5 % are measured in farther experiments as the gels of required viscousness ( depending on pH the viscousness varies from 671 mPa/s to 4850 mPa/s )

Harmonizing to specification, H2O, heated to at least 70oC must be used for dilution of the polymer. Without utilizing temperature merely suspension may develop

Blending does add uniformity of the gel although it is non relevant. Without utilizing temperature the gel is non proper to utilize


1 % , 2 % and 3 % are chosen and the viscousness varies in the interval of 127 – 3290 mPa/s

Harmonizing to specification, H2O, heated to at least 70oC must be used for dilution of the polymer. Without utilizing temperature, suspension is being made

Blending does add litttle spot to uniformity of the gel although the sectors of liquid and really thick gel are still there – without utilizing temperature the gel is non ready for use


None – the preparation is non homogenic and does non organize a gel – it forms a suspension

It is non soluble in hot H2O. There are no marks of gel preparation

Blending did non better the preparation – it still stays a suspension

* – concentrations, that autumn into interval of viscousness 1000-5000 mPa/s are used as optimum.

The significances of polymer per centum in the preparation are being chosen in assumtion that the in-between values should be the optimum 1s.

Fig. 1. Probe of pH value matching to the concentration of the polymer in the vehicle. CP – carbopol ; MC – methylcellulose, HM – hypromellose.

Fig. 2. The influence of temperature and commixture on the viscousness values. CP – carbopol ; MC – methylcellulose, HM – hypromellose, M – commixture.

Fig. 3. Addiction of viscousness value on polymer per centum in gel preparation. CP – carbopol ; MC – methylcellulose, HM – hypromellose.

Fig. 4. The dependance of viscousness on the pH value of gels. CP – carbopol ; MC – methylcellulose, HM – hypromellose.

Fig. 5. Correlation between the per centum of polymer, used for gel readying and conduction.

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