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Summary. Iontophoresis - is a method of using a small electric charge to deliver a medicine or other chemical through the skin. Iontophoresis nowadays is being used for either enhancing the penetration of molecules, such as porphyrins, aminolevulinic acid [1, 2] through skin or to reduce their permeability (such as fentanyl) .
Objective. The aim of the study is to formulate an optimal pharmaceutical iontophoretic delivery form and to examine the dependence of its quality and stability on the polymer used for the formation of basis, the viscosity of the vehicle and its electrical conductivity (in due to the necessity of the molecules to be in an ionic state).
Materials and methods. For the formulation four polymers (carbopol (carbomer), methylcellulose, hypromellose and hydroxypropylcellulose) have been selected. Also potentiometry, conductometry and viscosimetry have been applied.
Results. In the search of optimal pharmaceutical form, different polymers and different concentrations (0.25 - 10%) have been tested. During experiments different viscosities have been obtained (1.5 - 10000 mPa/cm). Various pH values for the formulation have been applied but little or no correlation has been noticed between the pH value and the viscosity.
Conclusion. The optimal pharmaceutical form for iontophoresis is a gel preparation of optimal viscosity (1000-5000 mPa/s) and conductivity. Concerning the percentages of polymer in the preparation the optimal option is 1% of carbopol, 4% of methylcellulose and 2 or 3% of hypromellose. Conductivity of the vehicle also influences the iontophoresis - in most cases lower viscosity induces higher conductivity (as the correlations are reverse). The pH should vary from 5 to 7.4 (because the incorporated substance must stay stable and skin must not be irritated) .
Introduction. For the delivery of anticancer drugs through skin by iontophoresis optimal pharmaceutical form is being designed. The main aim is to evaluate its oraganoleptic properties and the optimal viscosity/conductivity ratio for iontophoretic delivery.
Firstly, four polymers corresponding to the main factors of quality (suitability for gel formulations, lubrication and stability) [5, 6] have been chosen for the formulation of the vehicle. The chosen vehicles and their features are listed below:
Carbopol (carbomer) - polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol. They absorb water, get hydrated and swell. Carbomer has hydrophilic features as well as its cross-linked structure and its insolubility in water makes carbopol a potential candidate for use in controlled release drug delivery system [7, 8, 9].
Methylcelullose - is a polymer of long-chain substituted cellulose in which 27 - 32% of hydroxyl groups are in the form of methyl ether. It might be used for the formation of the gel basis, as a coating agent, emulsifying agent etc. [7, 8, 10]
Hypromellose - is a partly O-methylated and O-(2-hydroxypropylated) cellulose. It is an odorless, tasteless, white or creamy white fibrous or granular fiber, used as an emulsifier, suspending agent or stabilizing agent for topical preparations [7, 8].
Hydroxypropylcelullose - cellulose, 2-hydroxypropyl ether. It is a white to slightly yellow -coloured, odorless and tasteless powder used as emulsifying, stabilizing and suspending agent in semi-solid preparations [7, 8, 11].
Two main parameters are examined for the formulation of optimal iontophoteric form - viscosity and conductivity. Viscosity for this system should be 1000-5000 mPa/s (100-500 cps). Conductivity should be as high as possible for penetrating molecule to move as fast as it can through skin until the saturation of skin pores . The flux of the molecule correlates to the ionization of the molecule and the vehicle. Also for the formulation of gels such factors as heating and mixing is evaluated. For stability the monitoring of pH and viscosity day-to-day or week-to-week is being measured in carbopol gels. Evaluation of the quality and stability parameters should be relevant in the future in the design of iontophoretic gel as a vehicle for penetration of anticancer drugs through skin.
Materials and methods.
Chemicals. As the basis for gels carbopol 980 (CP) (Lubrizol, USA) has been purchased. Methylcellulose (Metholose SM) - MC , hypromellose (Metholose SH) - HM and low substituted hydroxypropyl cellulose NF - LSHPC have been received from Shin-Etsu (Japan) as a gift. For adjustment of pH potassium hydroxide (BDH Laboratory Supplies, England) and hydrochloric acid (Sigma-Aldrich, Germany) have been used.
Equipment. SV Series Sine-wave Vibro Viscosimeter (A & D Company, Japan) for measuring viscosity and WTW InoLab series conductometer (WTW Wissenschaftlich-Technische
Werkstätten GmbH, Germany) for measuring conductivity have been used. Mixing has been performed by magnetic stirrer MSC basic (IMLAB bvba, Belgium).
Laboratory testing. The evaluation and adjustment of pH values, measurement of conductivity and viscosity has been performed.
Results and Discussion
The screening of polymers for preparation of iontophoretic gels, the influence of mixing and heating on their quality, selection of optimal concentration of polymers
After methanalysis of literature [10, 11, 13, 14, 15, 16, 17] four polymers have been selected for the formulation of basis for iontophoretic gel. One polymer - CP is of a polyacrylic nature, the other three - MC, HM, LHPC - are cellulose derivatives.
First step was the selection of optimal concentration of these polymers and additional measures (if needed) for formulation of the gel. Additional measures included heating up to 70oC and mixing (Table 1).
pH stability through days
Normally, while dissolving 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 kind of polymer is almost the same (Fig. 1).
The resuls show that before pH adjustment independendly to the concentration of the polymer the pH of the gels of same polymer are very similar (RSD = Â±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 origin. Cellulose gels have higher pH.
The pH adjustment is being performed in the period of three days after the formulation. It depends on the time required for the formulation to become stable and for the polymer to swell and dissolve completely in the water [18, 19]. After the adjustement, re-adjustment is performed after one day and then pH is measured approximately in the period of 1 month .
Results of re-adjustment: in many cases the difference from intended pH meaning is few decimals or none before re-adjustment. But in some cases they may differ even in 1 pH unit - that is why re-adjustment must be performed.
Results after re-evaluation of pH in one month: in many cases the real pH value is the same as intended one - the differences vary from 0.1 to 0.3 points per number. So the pH value after the re-adjustment is statistically stable enough.
The influence of temperature on the stability of carbopol gels
For the evaluation of resistance to temperature and the influence of temperature on the viscosity of carbopol gels few pH values which will most likely be used for the formulation of pharmaceutical form are selected. The pH values are chosen accordingly to the ability to sustain the stability of anticancer drug (which will be incorporated into the formation) and the non-irritability to the skin .
The results of this experiment have been shown in the picture below (Fig. 2).
In general means the viscosity (resistance) should decrease while temperature increases but carbopol gels are complex polymer formulations and in the influence of temperature the structure reformulates itself. Therefore, the increase of viscosity in the presence of rising temperature is enrolled (Fig.2).
Also, it is quite obvious that gels which have been mixed have higher viscosity of about 15 - 20%. The mixing increased the viscosity of CP gels (pH=5 and pH=7)) (Fig. 2).
The highest viscosity of non-mixed CP gels is of the pH=6 gel, but other gels are suitable for iontophoresis as long as they form the right vehicle and their viscosity is enough.
The change in viscosity under the influence of temperatute (it rises by 30 degrees from 25oC to 55oC) varies from 4 to 10 %. Normally, the gels while storing do not reach mentioned conditions, so it might be considered that the gels are stable transdermal forms in room temperature.
Viscosity is one of the main factors influencing the formulation of optimal semi-solid pharmaceutical transdermal drug delivery form [9, 22]. For iontophoresis of hydrophylic molecules gels are chosen as optimal vehicles. Accordingly to literature [9, 10, 15], optimal range of the percentage of polymer put into a gel formulation is exluded. As it is shown in Fig. 3 below MC has the highest viscosity features, as well as CP has the lowest ones. After this evaluation, optimal concentrations form the ranges are excluded (CP - 1%, HM - 2 and 3%, MC - 4%). These values are chosen as the viscosity is in the optimal range or it becomes optimal after pH adjustment.
Considering the dependance of viscosity on the pH value the results are quite chaotic. The acid-base balance has different effects on gel preparations. The viscosity jumps up and down accordingly to pH but the correlation is not clear and linear. As an example, below you can see Fig.4 which represents the chaotic dependance of 1% CP, 1% HM and 3% MC gels on their pH values. In this example, the viscosity for CP is increasing up to a value of pH=8 except one point (pH=7) where it drops. For MC the viscosity dectrases until pH=6, then it increases up to pH = 7.4 and drops at pH=8. It is also chaotic considering the HM curve. In other examples, the highest peak of viscosity might be in the center or the end of the pH values. Considering other concentrations or polymers the same rules apply - there is no tendency on the increasment or decreasment of pH as polymers have a complex structure that is quite sensitive to pH changes.
Conductivity is especially important in iontophoresis because the transportation rate is directly connected to it [2, 23]. For the export to the skin, the molecule of the drug must be ionized. In this case we have not incorporated an active substance - the conductuvity has been measured for the gels as vehicles for iontophoresis.
The correlation between increasing percentage of polymer in the composition of the gel and conductivity has been established as it is shown in Fig. 5. Also, in comparison to Fig. 3, lower viscosity produces higher conductivity.
It is noticed that in most cases lower viscosity is connected with higher conductivity. Though the correlation mostly is not very strong. Correlation coefficients for different groups or polymers and their different concentrations vary: for HM the strongest correlation is in the group of HM 1% concentration (-0,63) - medium correlation, MC 1% - adequately -0.69 (medium), CP 0,5% - (-0.73) (strong). In other cases the correlation is mostly weak and reverse.
As optimal pharmaceutical form for iontophoresis must essentially posess the features of optimal viscosity and conductivity, firstly the materials for gel formation have been selected - these are CP, MC, HM, but not LHPC as it did not form the gel. It has been evaluated that the pH of gels has an influence to its features such as conductivity and viscosity, though the correlation might be weak. The correlation between conductivity and viscosity may exists as well, though, in many cases it is reverse and weak. So, the creation of optimal vehicle for iontophoresis depends on the substance that has to be incorportaed into the gel. Accordingly to its features the conductivity, viscosity and the pH of the vehicle must be adjusted. In terms of quality and stability manufactred gels are suitable for incorporation of the drug and application for iontophoretic therapy.
Table 1. The selecton of optimal basis and additional measures for the formulation of gel. CP-carbopol; MC - methylcellulose, HM - hypromellose. LHPC - low-subsituted hydroxypropylcellulose.
Optimal concentration (according to viscosity)*
0.5 and 1 % (depending on pH the viscosity varies from 213 mPa/s to 9580 mPa/s) are chosen for further experiments
Heated water has not been used for the preparation as it is not mentioned in the specification
Mixing enhances the viscosity by 15 - 20 % though gels without mixing are of a good quality, therefore, mixing will not be applied in further inversigations.
3%, 4% and 5% are measured in further experiments as the gels of required viscosity (depending on pH the viscosity varies from 671 mPa/s to 4850 mPa/s)
According to specification, water, heated to at least 70oC must be used for dilution of the polymer. Without using temperature only suspension may develop
Mixing does add uniformity of the gel although it is not relevant. Without using temperature the gel is not proper to use
1%, 2% and 3% are chosen and the viscosity varies in the interval of 127 - 3290 mPa/s
According to specification, water, heated to at least 70oC must be used for dilution of the polymer. Without using temperature, suspension is being made
Mixing does add litttle bit to uniformity of the gel although the sectors of liquid and very thick gel are still there - without using temperature the gel is not ready for usage
None - the formulation is not homogenic and does not form a gel - it forms a suspension
It is not soluble in hot water. There are no signs of gel formulation
Mixing did not improve the formulation - it still stays a suspension
* - concentrations, that fall into interval of viscosity 1000-5000 mPa/s are used as optimal.
The meanings of polymer percentage in the formulation are being chosen in assumtion that the middle values should be the optimal ones.
Fig. 1. Investigation of pH value corresponding to the concentration of the polymer in the vehicle. CP - carbopol; MC - methylcellulose, HM - hypromellose.
Fig. 2. The influence of temperature and mixing on the viscosity values. CP - carbopol; MC - methylcellulose, HM - hypromellose, M - mixing.
Fig. 3. Dependance of viscosity value on polymer percent in gel formulation. CP - carbopol; MC - methylcellulose, HM - hypromellose.
Fig. 4. The dependence of viscosity on the pH value of gels. CP - carbopol; MC - methylcellulose, HM - hypromellose.
Fig. 5. Correlation between the percentage of polymer, used for gel preparation and conductivity.