In anatomy, the human skin is composed of many layers of the tissues, but the skin is generally divided into

three layers of tissue: epidermis, dermis, and fat layer under the skin. The outermost layer is the stratum corneum or horny layer

The number of areas in its path may be between 0,1 % to 1 % of the area of the skin ( Lachman & Lieberman , 2008). Area for absorption appendages only provide a small (approximately 0,1 %) and these usually do not contribute enough. However, it may be important for these ions and large polar molecules witch difficult to

composed of dense cells, dead cells and keratin in layers with a density of 1,55. Due to the nature of the stratum corneum, the value of the diffusion coefficient of this tissues a thousand times (even more) is smaller than the other skin tissue, resulting in higher durability and generally can not be penetrated by the drug (Lachman & Lieberman, 2008). Although the skin has been divided histologically into the stratum corneum, epidermis, and the dermis, third of them is a barrier layer. The penetration of this layer can occur in a way, transcellular penetration (passing through the cell), intercellular

traverse corneum layer (Aulton, 2001). Piroxicam is a NSAID with a new structure that is oxycam, derivate enolate acid. These drugs undergo enterohepatic cycle. The frequency of adverse events with piroxicam reach 11-46 % and 4-12 %. Number of patients forced to discontinue the drug. Common side effects disturbances (Gunawan, used as a are and 2007). topical

gastrointestinal peptic ulcers is

Piroxicam

treatment in inflammatory conditions as a topical gel at a concentration of 0,5 % three to four times daily (Sweetman, 2009). Some medications have side effects that can not be eliminated in any dosage form, many drugs show unwanted behavior that specifically related to the route of administration. One effort to eliminate some of the problems of traditional dosage forms is

penetration (gap between cells), transappendages penetration (through the hair follicles, sweat glands, oil glands, and sebaceous glands) (Ansel , 2005). Penetration of the epidermis surface area of 100 to 1000 times greater than the other penetration. The parts of the body, sweat glands and hair scattered pockets spread in the skin in varying amounts, but rarely.

the development of a transdermal delivery system. The advantages of transdermal system is to avoid chemical digestion Gastrointestinal (GI), there is no

into the stratum corneum (Aulton, 2001). Some examples penetrant is water, sulfoxide, Azon, pyrrolidone, fatty acids, alcohols, fatty alcohols and glycols, surfactants, urea, essential oils, terpenes and terpenoids,

danger of GI or other physiological contraindications exist on the oral route, can provide adequate

phospholipids, and high concentrations of solvents ( William & Barry , 2004). Based on the description above, the researchers of will some look at the

absorption of certain drugs, there is an increase in patient compliance , avoids first-pass effect , allowing the use of effective for drugs that have a short half-lives, allowing for the

influence

penetration

enhancers on the rate of increase in penetration of piroxycam gel. The problem that arises is whether oleic acid, DMSO, isopropyl myristate, and propylene glycol may increase the rate of diffusion of piroxycam in gel

administration of drugs with a narrow therapeutic (Ranade and Hollinger, 2004) . It is common knowledge that the bioavailability of most drugs topical use is still low. Various methods to increase the bioavailability has been used. One of them is the use of penetration Penetrant enhancers should (penetrant). not have

preparation. The purpose of this study is to obtain a formula with the most good penetrant effectiveness in increasing the rate of diffusion of piroxycam in gel preparation.

pharmacological activity, non- toxic, has a rapid onset and reversible, chemically and physically mixed with other formulation ingredients, and The diffusion tools cell used types, are Franz

glassware,

homogenizer (IKA -WERKE), digital cameras, measuring (Biohit balance flask course, ), ),

convenient to use ( Swarbrick , 2007). Penetrant can work through three mechanisms, namely by

micropipette analytical

Proline (Sartorius

disrupting the structure of the stratum corneum , intercellular proteins interact premises, and improve drug

analytical balance (Denver ), pH meter (Sartorius ), UV-VIS ),

spectrophotometer thermometers,

(Shimadzu

partitioning, coenhencer ,or cosolvent

vials,

viscometer

(Brookfield ), Magnetic stirrer (IKA ). The materials used are distilled water, aluminum foil, oleic acid,

homogeneous,

add

glycerin

and

residual water into a gel base. Formula with the addition of penetrant is made in the same way, but penetrant add before adding the remaining water

Carbomer 940, disodium hydrogen phosphate, glycerol, DMSO, isopropyl myristate, phosphate, potassium potassium dihydrogen chloride,

Evaluation of Piroxicam Gel Preparations 1. Organoleptic (Mangngisengi, 2013) Organoleptic tests include color , odor , and clarity observed visually. observation

parchment paper, snake skin, methyl paraben, sodium chloride, piroxicam (Kimia Farma ), propylene glycol, triethanolamine.

Preparation of Piroxicam Gel (Soebagio et al, 2009) Created 13 gels formula

2. Observations (Mangngisengi, 2013)

Homogeneity

The preparation is applied to the gel after the making of a piece of glass is then covered with a piece of glass and observed homogeneity. 3. Measurement (Mangngisengi, 2013) Gel measured Sartorius. preparation using a pH pH was meter of pH

containing piroxycam as an active ingredient, Carbomer 940 and

Triethanolamine as base gel, methyl paraben as a preservative, glycerin as a humectant, and DMSO, oleic acid, and myristic isopropi as a penetrant. Formula can be found at Tabel.1:

Methyl paraben is dissolved in hot water. Carbomer 940 is dispersed in water containing Methylparaben for 24 hours until fluffy. After that

4. Viscosity (Mangngisengi, 2013)

Measurement

Gel preparation put into the shot and then the viscosity was measured using a Brookfield viscometer . 5. Coverage (Mangngisengi, 2013) The preparation gel with 1 gram weight placed carefully on the glass measuring 10 x 10 cm which has been Measurement

triethanolamine was added dropwise while stirring slowly. Piroxicam

dissolved in Triethanolamine with a little water. The solution was put in a gel base and stirred until

weighed beforehand , and then closed again with the glass that was given a load of 125 grams and wait for 60 seconds . The spread of the gel was calculated by the formula : S = m xL / T where : S = Coverage (g cm sec-1) m = Load given (g) L = length of the diameter of the spread (cm) T = time required for spread (seconds)

water up to 900 mL. The degree of acidity of the solution was measured with a pH meter. pH adjusted by the addition of 0,01 M NaOH higga reach pH 7,4. Then ditambahakan with CO2free water up to the mark . 2. Determination Wavelength Triethanolamine and piroxicam dissolved in phosphate buffer pH 7,4, made 10 ppm concentration. Then the absorbance was measured in the wavelength range of 200-400 nm. of Maximum

6. Examination Levels of Piroxicam (Agustin et al, 2007) Weighed 1 gram dosage

Subsequently

made

between

the

uptake of the concentration curve . 3. Preparation of Standard Curve Triethanolamine and piroxicam dissolved in phosphate buffer pH 7,4 and made the concentration of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 ppm. Furthermore, each concentration is determined at a wavelength of

equivalent to 5 mg of piroxicam and dissolved in PBS pH 7,4 to 5 mL , and 50 mL was taken and diluted with PBS pH 7,4 to 5 mL, in order to obtain a solution of piroxicam 10 mg/mL . Then the concentration was determined by UV spectrophotometer.

maximum absorbance, then made between the uptake of the

Content Piroxicam in

Determination UV -

of Vis

concentration curve.

spectrophotometry

Diffusion test 1. Membrane Preparation Snake Skin

1. Preparation of Phosphate Buffer Saline ( PBS ) pH 7.4 Weighed 8 g NaCl, 0,2 g KCL, 1,44 g Na2HPO4, and 0,24 g KH2PO4. Included in the course measuring 1000 mL flask was dissolved with CO2-free

(Naidoo, 2012) Dorsal part snake skin washed with water. The membranes were dried at room temperature by means of filter paper laid over for mempercapat drying. Membrane was cut with a

diameter of 2,5 cm and soaked in a solution of phosphate buffer for 1 hour before use. 2. Diffusion Testing Using Type Franz diffusion cells like (Agustin et al, 2007) Diffusion test performed using Franz diffusion cells like. Weighed 1 g of gel, placed in the donor

diffusion test of the standard curve calculations. The cumulative amount diffused calculated piroxicam use the following formula (13): Q= where : Q = cumulative amount penetrated (g/cm2) V = volume of cell = 40 mL or 50 mL S = volume of sample (3 mL) A = surface area of membrane (3,142857 cm2) Cn = number of penetrated on making to -n (mg/mL) Ci = number of diffused at a sampling interval of 1 to n-1

compartment membranes and gels snake skin trim, receptor compartment filled with PBS pH 7,4 at 37 0,5 C, and at 120 rpm rotation, a process carried out for 28 hours. Footage taken from the receptor fluid as much as 3 ml beaker and every decision is always replaced with PBS pH 7,4 as much as 3 ml. Footage taken with an interval of 2 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 24 hours, 25 hours, 26 hours, 27 hours, and 28 hours. 3. Content Determination of Diffusion Test Results (Agustin et al, 2007) Number of piroxicam are

Penetration velocity ( flux ) of piroxicam is calculated by the following formula (13): J=Q/t where : J = speed of penetration (g/cm2.jam) Q = cumulative amount penetrated t = time ( hours )

diffused per unit time is determined by measuring the specific absorbance at the maximum wavelength and is

calculated using the standard curve .

F. RESULTS AND DISCUSSION Evaluation of Gel

E. Data Collection Data collection is based on the results of spectroscopic piroxicam gel

Evaluation of the stability of the preparation is done to look at the appropriateness preparations and of the physical to

preparations

resume on pegujian diffusion. The results of the evaluation of piroxicam gel preparation with penetration

enhancers

have

the

highest

pH.

Formula containing propylene glycol has a pH of 9% lower than the fomula other containing propylene glycol,

enhancers share: 1. observations organoleptic

Table 2. Observations organoleptic

while the formula containing DMSO lowest pH indicated at a concentration of 5% DMSO, isopropyl myristate to

Based

on

organoleptic

the

formula

lowest

pH

at

observations, Formula containing oleic acid and isopropyl myristate have interaction with the gel base,

concentration of 3%, and for oleic acid formula lowest pH at a concentration of 4%. pH preparations are not on the normal skin pH range is 4,5-6,5 (Tabor, 2009). This is because the amount of 3% Triethanolamine which give an alkaline pH of the preparation. Piper, find a good buffer capacity of the skin between pH 4 and pH 8, the optimum value in accordance with pKa 6,5 Amino acids in the epidermis (Barel, 2009). Test results dispersive power gel preparation did not show significant differences between formula one with the other formulas. Value dispersive power is not an absolute data because there is no literature stating exact figures, so that the value of the dispersive power is relative data. Test results show the dispersive power gel preparation of formula 3% oleic acid showed the lowest dispersive power

triethanolamine which is the emulsifier so as to form an emulsion with oleic acid and isopropyl myristate in the form of oil. This result is not

transparent gel. Some preparations gave the appearance that the

transparent gel like water, while others turbid gel because the materials are not fully dispersed the molecular or material form aggregates, which

disperse the light (Allen, 1996). Observations of homogeneity showed all homogeneous gel formula. This indicates the absence of a liquid phase separation above the surface of the gel mass gel called sinersis (Lieberman, 1996). This indicates that piroxicam evenly dispersed in the gel preparation.

Results of pH measurements showed Formula gel preparation that does not contain penetration

and 5% oleic acid formula showed the highest dispersive power. Value

dispersive power is not an absolute

data because there is no literature stating exact figures, so that the value of the dispersive power is relative data. the

The results of measurement of gel showed that piroksokam

formula containing 5% oleic acid does not give absorbance piroxicam so do

The

results

of

viscosity

not do testing on Franz diffusion cells.

measurements gel preparation showed a concentration of propylene glycol affects the viscosity of the gel, a small semikin viskositnya vanishingly small concentrations. Formula containing Based on the test results

demonstrate diffusion formulas F0, which does not use penetration results of

enhancers

diffusion

DMSO showed that the pH affects the viscosity of the gel preparation, the lower the pH the more rndah viscosity. Formula containing isopropyl myristate with lowest pH had acid the lowest

piroxicam smallest with the lowest rate of diffusion as well. The ability of propylene increases glycol as a penetrant increasing

with

concentration. Propylene glycol as solvent work over the tissues can change the thermodynamic activity of the drug in a carrier that can lead to diffusion, Propylene glycol is

viscosity.

Oleic

concentration

affects the viscosity of the gel, the higher the concentration the higher the viscosity.

partitioned into the skin tissue and Rheological curves of the above it can be concluded that the gel has a plastic flow where there is a value on the yield curve. This value yields the value of the stocks do not often make biased or refuse to be poured from the bottle until the bottle is shaken or beaten. Once the yield value is facilitate the entry of drugs (William, 2004). Propylene glycol also function as humectants that hydrate the

stratum corneum and improve the trajectory of all drug penetration. This is due to the softening of the tissues and due to the addition of pore size (Ansel, 2005). The optimum concentration of isopropyl myristate as penentran

exceeded and flow begins, plastic flow may show karakteristi pseudoplastic flow where the viscosity decreases with increasing shear rate (Brookfield Enginering Laboratories).

indicated at a concentration of 2%. The mechanism of isopropyl myristate is to increase the damage of the stratum corneum lipids (Barel, 2009).

The optimum concentration of oleic acid as a penetrant is 3 %. Oleic acid interacts with and modifies lipids in the stratum corneum and provide

profile as many as 447,12 g/cm2 over 28 hours of permeation time . REFERENCES

permeability damage to the stratum corneum. Formula containing 5 % DMSO diffusion results of piroxicam greatest among other formulas and have the highest diffusion speed. This is

because the mechanism of DMSO as a penetrant is to denature the protein keratin and intercellular change the conformation of the human skin. Just as good as the effect on the protein, DMSO also interact with the

intercellular lipids of human stratum corneum. According to the results of the diffusion test adding propylene glycol, DMSO, isopropyl myristate, and oleic acid in a gel preparation will affect the increase in the concentration of

piroxicam piroxicam diffused optimum concentration of the preparation in each. conclusion From the research concluded that propylene glycol, DMSO, isopropyl myristate, and oleic acid can increase the penetration of piroxicam gel

preparation. Preparations containing 5 % DMSO gave the best permeation