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In vitro studies are carried out in lab under controlled environment (outside living organism). In vitro experiments are carried out in test tube or petri dishes. In in vitro studies scientists isolate specific cells, bacteria, viruses and study them in detail instead of the whole organism.
In vitro study describes the effect of experimental variable on an organism's constituent parts. Organs, tissues, cells, biomolecules are studied in in vitro research. In vitro research deduces biological mechanism of action and with, fewer variables and perceptual reactions to subtle cause gives better results.
In vitro research is cost effective and less time consuming as compared to in vivo studies. Hence in vitro research is vital and is highly productive.
Skin provides an effective route for local administration of drug. However skin (stratum corneum) proves to be a barrier for drug absorption(1). Hydration is the cause for thickness and penetration property of stratum corneum. Hence, scientists have to prepare formulations which enhance and improve drug absorption. To increase the percutaneous absorption enhancers are used(1).
Enhancers react with skin constituents to induce a temporary and reversible increase in skin permeability. The physicochemical property of enhancer is compared with those of the drug. Therefore, depending upon the drug the enhancer is selected. The enhancers increase the diffusivity of the drug in the skin. Thus enhancers are used to increase the penetration rate or permeation rate of drug through skin(1).
Piroxicam is the potent, non steroidal anti inflammatory drug.
There are various studies conducted to check for the penetration and the absorption of the drug from the tropical surface and the entire means id based on the solvent and the absorbents used and the nature of the solution, similar studies are been discussed below.
Franz glass diffusion cell system is one of the method generally preferred. The study consisted of 6 cells and an autosampler, Cellulose acetate membranes (Porafil, Machenerey-Nagel, Germany) with an average pore size of 0.45 were used(2). The medium used for the receptor phase was phosphate buffer at pH 5.4. Receiving medium was similar to that of skin to allow enough amount of the active ingredient to be available for the analysis(2). The absorbance was measured by UV spectrophotometer at 359 nm. Piroxicam was the drug of choice to be tested and in case of in vitro studies it helped in proving highest release is with the help of hydroxyl gel, this was measured with the help of the synthetic membrane soaked in buffer solution. And the similar result was seen in case of liquid crystal system(2).
Similarly there was other study conducted for the same drug but with organogel which are known to be useful tropical deliveries for liophylic drug, transdermal absorption also helps in getting the systematic effect. In the present study, two-component organogels based on liquid glyceryl fatty acid esters and including solid glyceryl fatty acid esters as organogelators were tested for their ability to enhance the skin penetration of piroxicam, here the effect were compared with the marketed product(3). In this case Franz vertical diffusion cell was used for in vitro studies The samples were placed on a cellulose acetate membrane which was soaked in isopropyl myristate, similar to the previous study the acceptor phase was phosphate buffer at pH5.4 and was determined spectrophotometrically(3). The anti inflammatory effect of the organogel was again compared with the commercially available product and also the bioavailability was checked The in vitro penetration profile of Px from glyceryl fatty acid ester organogels was described by the Higuchi equation and was found that it might influence certain features like, the partition between the vehicle and the lipophilic layer, the lipophilic/hydrophilic partition between the lipophilized membrane and the acceptor phase, the solubility of the poorly water-soluble Px in the acceptor phase(3).
The other study with the same drug was carried out but was with a different aim, in this case concentration of the drug was majorly focused and studied, this concentrations were to be studied on the effect on the percutaneous absorption of the drug and to study this effect in vitro methods were used(4). The three different concentrations studied were 1% OA, 5% LEC and 10% IPM, amongst the final result obtained was that 1% OA gives the best permeability rate of piroxicam and also is greater than other two concentrations(4). The effect went on reducing for permeability of the piroxicam drug from 5% LEC to 10% IPM. OA in all concentrations used has the greatest ER among the penetration enhancers that were studied(4).
There was other study conducted with the similar aim regarding the penetration of the drug and it was carried out in the abdominal rat skin by in vitro methods. Carbopol gels containing 40% propylene glycol as cosolvent was the solvent used to get the good permeability rate and the assay used was the same as the previously used ones that is Franz diffusion cells(5). Isopropyl myristate, oleic acid and linoleic acid led to a large increase in piroxicam flux compared with control gel(5). The results obtained here were the similar to that of the orevous studies that is the same OA was the enhancer which gave the best permeability of the drug and the effectiveness was 7-8 folds more as compared to the control gel(5). There was another conclusion derived from the stud that unsaturated fatty acids can be used to get the better percutaneous absorption if the drug. The other enhancers used were alcohol and esters but they were not proved to be more effective as compared to the effectiveness of an OA(5).
The studies were later on modified and were conducted with a different aim and the next target was to check the effect of the salt formation on the percutaneous absorption, the source to check the effect was the hairless mouse skin, the PSA (pressure sensitive adhesive) matrix were investigated for the different combinations of the salts(6). The various different salts used were derivatives of piroxicam-ethanolamine (PX-EA) salts from an acrylic adhesive matrix. piroxicam-monoethanolamine salt (PX-MEA).piroxicam-diethanolamine salt (PX-DEA). piroxicam-triethanolamine salt (PX-TEA) (6). These were the different derivatives of the salts used to check whether they can help in better penetration of the drug by percutaneous route. They all showed different results in the penetration rate even though they were derivatives of the same salts at the same time when the various enhancers were used especially when they were Crovol A40, Crovol PK40 or Plurol oleque. No proper conclusion was derived from the study(6).
The basic mechanism of percutaneous absorption of a drug into the body is by two processes: the first being the release of the active ingredient from the topical formulation and the second is adsoption into the skin at the site of application(7). An area of improvement for percutaneous absorption would be to increase the release of the drug from the dose administered as the rate of release of the drug depends upon the physiochemical characteristics of both the drug as well as the vehicle involved(7).
The most efficient way to observe the drug action would be for the for the artificial vehicle used to act the same way as the human skin layers and the barriers involved within the body. Thus for the very same, a membrane filter induced with a specific skin lipid, isopropyl mystristate has been used in numerous studies(7). One of the most commonly used anti inflammatory drug which provides better activity with less side effects on topical administration is piroxicam. To identify the amount of percutaneous absorption by piroxicam the following case study was conducted using in vitro methods(7). This study observed the in vitro relase rates of piroxicam via specific carbopol gels and alsoc checked the solubility and concentration levels of the active ingredient in the vehicle of choice. Also the viscosity level of the topical drug was tested through the use of synthetic membranes and by testing on stomach skin(7). The main objective of the study was to determine the legitimacy of IPM induced skin membranes.
The industrial batch of piroxicam along with the other reagents was converted to solution gels with the help of magnetic stirring and the solubility determination of the drug under inspection was done using UV spectroscopy(7). The release rate of the topical infusion was tested by passing the solutions through a membrane mounted onto a gel plate which was then kept in a vacuum compartment fileld with phosphate buffer. The temperature and pressure was maintained at 37 degrees and stirred at 600rpm. The samples so collected were then sent for permeation studies done on abdominal skin of rats and also on a lipophilic membrane(7).
It was observed that maximum solubility of the drug was seen when a cokbination of phosphate buffer and propylene glycol was used. The membranes used for the tests did not have any significant effect on the release of the drug or on the properties of the formulation controlling the release(7). Further, piroxicam release was shown to increase with a reduction in propylene glycol voncentration within the vehicle used as propylene glycol acts as solubilizer. A much debated decrease in the rate of relrease was observed when the amount of solution within the vehicle was increased than normally required to dissolve the drug(7).
Other positive outcomes of the test were that the rates of release increased with an increase in solubilizer concentration. Doubling the concentration of the active ingredient doubled the chances of its release rate(7). Even a slight increament in the concentration of the drug reduced the viscosity of the gels. Thus it could be said that the IPM levels did not differ with variation in diffusion rates of the drug(7).
Of all the gels tested, the one with 40% propylene glycol and 1% piroxicam gel showed the maximum release rates and the best flux characteristics in all of the membranes tested. The IPM membranes thus represented most amicable results as models for topical infusion of these drugs due to theor increased reproducibility, easily manufactured and better availability(7). Thus it can be concluded thorugh this study that the membranes used were only as a release rate controlling step in the process of topical percutaneous absorption of the drug rather than a drug release from the formulation(7).
Piroxicam is an anti inflammatory agent when given orally causes severe side effects. As a novel treatment topical route of administration is being studied for piroxicam. It is assumed that topical route of administration would cope up with the side effects. As drug delivery through topical route is difficult enhancers are used to increase the permeability rate of the drug.
A study reveals piroxicam shows better permeability rate through cell membrane impregnated IPM. The study shows that 1% piroxicam and 40% propylene glycol combination gel increases the permeability rate to a greater extent incase of cell membrane impregnated with IPM as compared to abdominal rat skin. The abdominal rat skin proves to decrease the permeability rate. The study shows that permeability rate increases with increase in piroxicam and decrease in propylene glycol. The combination gel with more than 40% of propylene glycol shows decrease in permeability rate causing increase in solubility. Another reveals that hydrogel shows better permeability rate as compare to liquid crystal system and o/w cream when cell membrane impregnated with IPM is used.
A study shows that glyceryl fatty acid esters influence the rate of permeability of piroxicam.it shows that some fatty acids like glyceryl mono-and distearate SE and glyceryl stearate increases the solubility of piroxicam, while decreases the permeability rate. Fatty acid like glyceryl monosterate decreased solubility and increased the permeability rate. Thus depending upon the permeability rate the fatty acids are used as an enhancers.
Comparing different vehicles the permeability rate also differs to a greater extent. IPM showed greater permeability rate as compared to UR and LEC, while LEC showed greater permeability rate as compared to UR. But OA with 1%w/w concentration showed greater permeability rate as compared to IPM, LEC, UR.
In comparing various vehicles like IPM, oleic acid, linoleic acid, DMSO, oleyl alcohol, oleic hexyl ester, with control gel , the results showed IPM, oleic acid, linoleic acid showed greater permeability rate as compared to control gel, while DMSO, oleyl alcohol, oleic hexyl ester showed slight increase as compared to control gel.
Later study showed 5%w/w concentration of OA showed highest permeability rate for piroxicam.
There were different studies conducted from similar point of view as well from different point of view, as discussed in the literature review, above. The basic aim behind the entire the review was to analyse the best enhancer for the penetration of the drug piroxicam via percutaneous route.
There were various dofferent enhancres and at different concentrations were tried out but the best obtained result from various studies was 1% OA which gave the optimum penetration rate and also simultaneously there was a different method tried out using salts and their derivatives, but that did not gave the optimistic outcomes.
From the case that was studied also stated that the OA is one of the best enhancer to give the higher rate of bioavailability of piroxicam, which is more important in case of oharmackinetic study.
Piroxicam being a potent drug it needs to be absorbed at a higher rate and should give the best possible bioavailability and this was found to be possible with the help of OA too a lower concentration and also it was possible using it as a good enhancer for the penetration via percutaneous transdermal route.
1. Charles S. Asbill and Bozena B. Michniak; Percutaneous penetration enhancers:
local versus transdermal activity, PSTT Vol. 3, No. 1, January 2000
2. I. Cs´okaa,e, E. Cs´anyia, G. Zapantisa, E. Nagyb, A. Feh´er-Kissc,
G. Horv´athb,c, G. Blazs´od, I. ErËosa,-; In vitro and in vivo percutaneous absorption of topical dosage forms: case studies; International Journal of Pharmaceutics, 291, (2005), p. 11-19
3. T. P´enzes a, G. Blazs´o b, Z. Aigner a, G. Falkay b, I. Erosa; Topical absorption of piroxicam from organogels-in vitro and in vivo correlations; International Journal of Pharmaceutics, 298, (2005), p. 47-54
4. Seyed Alireza Mortazavi, Reza Aboofazeli; An Investigation into the Effect of Various Penetration Enhancers on Percutaneous Absorption of Piroxicam; Iranian Journal of Pharmaceutical Research, August (2003), p.135-140
5. S. Santoyo , A. Arellano, P. Ygartua, C. Martin; Penetration enhancer effects on the in vitro percutaneous absorption of piroxicam through rat skin; International Journal of Pharmaceutics , 117, (1995), p. 219-224
6. Hyun-Ah Cheong, Hoo-Kyun Choi; Effect of ethanolamine salts and enhancers on the percutaneous absorption of piroxicam from a pressure sensitive adhesive matrix; European Journal of Pharmaceutical Sciences, 18, (2003) , p.149-153
7. S. Santoyo, A. Arellano, P. Ygartua, C. Martin; In vitro percutaneous absorption of piroxicam through synthetic membranes and abdominal rat skin; Pharmaceutics Acta Helvetiae , 71 , (1996), p. 141-146