Release of pharmaceutical substances
from dental materials
Introduction
Oral disease is normally caused by microbes – it is bacteria, that is responsible for caries as well as periodontitis, both the most common disease worldwide. Almost every individual of manhood is a patient for dentistry! But – if we agree, that oral disease is an infection, we have to use methods of infection control, including chemistry and not just mechanical treatment. And, the change in dental treatment is evident: modern toothpaste, for example, contains antibacterial ingredients, like Chlorhexidine, metal-ions (Zinc, Tin), Fluorides, Triclosane, and so on. Most of caries reduction is caused by this – and, additional, by processed food with conservatives, also with strong antibacterial potential.
To be serious – a lot of dental prophylaxis is done by the food and cosmetic industry.
What is left to the dentist? We also have to treat patients with antibiotics, to save tooth material and soft tissue. Just mechanic treatment is not enough, that´s the message.
The release of medications out of dental materials is not new – our grandmas gave the advice to chew cloves in a situation of tooth aches. The dentists of former centuries (e.g Philip Pfaff, dentist of the Saxony King in the German city of Dresden in 18th century) took this advice into dental science and used the power of cloves to build a cement with the clove’s oil and zinc oxide, a cement that was used till today as a temporary cement (“EBA cement”). The Eugenol, the oil from cloves, has powerful qualities in suppressing tooth aches, it is anti-inflammatory. Today we don´t use it so much because of the suppressive quality against pulp regeneration.
Another well known material with pharmaceutical qualities is amalgum. When fist in the US amalgum was used for a broader public, patients got profits of the corrosion of amalgam. Amalgam, an alloy of mercury, silver, tin, copper and zinc, is not absolute anticorrosive. Especially tin and copper corrode – not to forget, that silver also is corroding in oral environment – , and the corrosion products, the oxides or sulphides, are little soluble. And they can have influence on the bacteria – there is evidence of a very effective suppression of bacteria growth in the surrounding of amalgam fillings. So we made profits with this special quality – the margins of amalgam fillings had not to be perfect, nevertheless the restoration was stabile for a long term.
Based on this knowledge and the change in restorative dentistry with the use of resin restoration materials there had to be some research for new materials with release of pharmaceutical substances, not to forget other development, for example in endodontics, where without pharmacy the success is poor.
So, what kind of dental materials with release of pharmaceutical substances do we have on hand?
Filling materials
As mentioned above, there is amalgam. Than we got new improved materials with release of fluoride. Fluoride is well known as a substance that is able to reduce bacteria; at least it is proven that fluoride reduces the number of new caries lesions. Beneath fluoride there is not much – other substances with influence on oral micro organism are in development but not on the market.
Liner
But, it is possible to combine. So some layers are available with release of chlorhexidin-di-gluconat (CHX) or other bacteria suppressive quality, there are varnishes on the market (to use in intial lesions) with CHX, and there is a very old and nevertheless powerful material on the European market, “Ledermix” (Riemser AG, Germany), a combination of Doxycycline and a corticoid, developed by Prof. Dr. André Schroeder of Bern/Switzerland. In a newer study made by Prof. Dr. Noack of the German University of Cologne and his co-workers there was won evidence that Ledermix, placed directly on dentine in deep carious lesions, is able to reduce bacteria more effective than CHX varnish or Calcium hydroxide. This may be one of the reasons why in Sydney/Australia it is part of clinical curriculum at the dental school the use of Ledermix cement as a liner in case of deep carious lesions is obligate.
Ledermix is available in two modifications: you can get paste, the concentrated form, with thioxotrop qualities, mainly consisting of corticoid and Doxicycline, or you can use Ledermix cement, an EBA cement, with less medical substances but mainly zinc oxide and eugenol as basic content.
Used as a line beneath fillings it is effective as a bacteria killer and also to suppress pain resulting from inflammation. Inflammation, this is a statement of André Schroeder, causes a sharp rise of intrapulpal pressure and is followed by pain and if not treated loose of vitality. A negative side effect is, that there is a suppression of pulpal regeneration also – but, as some studies show, the content of corticoid, that is responsible for this effect, will not last forever – in a couple of days the release will lower and after months there will be no measurable release of corticoid anymore.
Another liner could be glass-ionomer. Glass-ionomers were introduced by Fuji/GC (Japan) in the 70th and later Prof. Dr. Mc Lean/London, GB, in the 80th in cooperation with ESPE (now 3M Espe) (Germany). The reason why glass-ionomers could be helpful as liners beneath fillings is that this cements release respectable amounts of fluoride. Fluoride is negative for bacteria metabolism; there is evidence that bacteria growth is hindered.
Today GC is the world leading manufacturer of glass ionomers, and in combination with resin restorations (“sandwich technique”) GC´s Glass-ionomers are of good use to seal dentine and prevent open dentibuli form possible negative influence of adhesive materials as used with resins. Also in early fissure seal for caries prevention glass ionomers are useful, and in minimal invasive strategies of tiny lesions glas ionomer often is the only material that can be used in interdentally sites.
Glass-ionomers are built of a special glass in form of micro pearls, with a lot of fluoride as elementary content, and poly-acrylic or maleinic (ESPE, e.g. Ketac) acid.
Mixed, the acid and the glass build a matrix of gel – it is no polymerisation like we find with resins, but a sole ionic reaction between base (glass) and acid (poly-acrylic acid). Therefore we have to wait, before going on – the reaction is in the beginning fast and then slowing down, contrary to the polymerisation of resins. Newer glass-ionomers are not plane glass-ionomers, but the materials have built in some resin contents, so the obvious reaction is much faster – most can be hardened by light like the resin. But, never forget: it’s just a fixation, not a complete reaction! So if used as a liner, it should be avoided to put phosphoric acid, as used for the adhesion of resin fillings, directly onto the glass-inomer liner. It would probably result in pain for the patient.
During cavity preparation, a thin so-called „smear layer“, grinding debris, is formed, which adheres to the prepared surface. It is important to remove most of this smear layer and to treat the dental surface with cleaning solution. Cleaning the surfaces also improves retention of both liner film or cement, especially glass ionomer cemets.
So the producers of glass ionomer cements deliver also cleaning liquids to remove the smear layer. Such common cleaning agents can be diluted solutions of polyacrylic acid or EDTA in water. These agents should not be applied to cavities with sensible dentin. The dentinal tubules may be opened an widened, with great risk to the pulp through increased permeability. This in turn creates the practical problem of drying the cavity when the dentinal tubules are patent.
Another product class is Tubulicid red (containing fluoride) and blue (plain) by “Dental Therapeutics”. TUBULICID BLUE is used for cleaning lager surface areas, for example before cementing crowns and bridges.
TUBULICID RED should be used for cleaning cavities and distribution of fluorine to enamel and dentin, for example in the treatment of hypersensitive cervical dentin.
Tubulicid removes smear layer without opening the dentinal tubules. Tubulicid Blue Label contains
Cocoamphodiacetate
Benzalkonium Chloride
Disodium Edetate Dihydrate
Phosphate buffer sol.
Aqua dest.
Very modern is the use of adhesives for resins placed directly onto the dentine. These adhesives are liners too, if you take a look at their chemistry. So some adhesives for direct use are filled with amorphous silica and have got some interesting further qualities.
Basically all such “one” or “two” step adhesives are monomers of resins with catalysts, so it is possible to polymerise under the influence of light. Further they have built in acidic contents, so a conditioning of dental structures is possible. But, with dentine they are very good, not with enamel – it is still better to etch enamel for a maximum of adhesion!
Kuraray, a Japanese manufacturer, has shown at IDS in Cologne/Germany this year a new adhesive that has proper antibacterial qualities either, so it seems to be the first liner/adhesive with a release of pharmaceutic effective substances.
This adhesive, named “CLEARFIL protect bond”, with integrated MDPB-monomer, works by destroying the bacterial cell membrane. Scientific evidence is given that a reduction of bacteria up to 70 percent is possible without any problem concerning biocompatibility or adhesive strength. So this product is called the very first antibacterial adhesive worldwide.
Another class of liners are combined at a basis of calcium hydroxide. Calcium hydroxide releases not real pharmaceutical substances; it works just with a change in pH-range that means, the pH goes up to 13 or 14, and bacteria don’t like this so much. Calcium hydroxide is known very long, so it has become the “gold” standard. Every other product is measured in comparison with it.
Dental Therapeutics, specialist for dental products, produces products named “Tublitec Primer” and “Tublitec Liner”. Tubulitec Primer consists of shellac (a natural resin) dissolved in alcohol with i.a. benzalkonium chloride. The microthin layer (ca. 1/1000 mm) is not affected by the ethyl acetate solvent in the liner.
Tubulitec Primer is hydrophilic, penetrates dried dentin, spreads out into a thin layer and is easy to applied. Tubulitec Liner Contains i.a. polystyrene and copaiba balsam dissolved in ethyl acetate and is applied over the primer. It is most important that the liner covers all the cavity walls and particulary the entire cervical margin. The risk for leakage is greatest here because the dentinal tubules (ca. 20 000 per mm²) are crosscut and patent all the way to the pulp (sensitive dentin). Furthermore there is frequently no enamel at the cervical margin.
So this both products can save pulp alive and prevent patients before unneccesary pain. TUBULITEC PRIMER and LINER can be used as insulation under all conventional restorative materials. Several experimental investigations have shown them to be excellent as „liners“ under composite materials and should be durable, provided resin impregnation is used to eliminate a possible cervical contraction gap between the composite and the insulation (see below). In experiments a gap has been observed nearest the dentin in a few cases only.
At least there are varnishes available with contents of antibacterial substances, especially the well known chlorhexidin-di-gluconat (CHX). For example, you can use a varnish made by Ivoclar Vivadent (Schaan/Liechtenstein), “Cervitec” that releases CHX, but there is also a high fluoride release with “Fluor Protector”, also manufactured by Ivoclar Vivandent, that can be used as a liner, nevertheless that varnishes originally were not built for this reason.
Cements
Aim of cement with pharmacologic contents is the reduction of bacterial noxes and the reduction of inflammation, felt as pain. First, an EBA cement on the basis of eugenol works mild pain reducing and so it is to see under the aspect of our main theme. Eugenol is a natural product – oil won out of cloves -, that can also be synthesized. It works anti-inflammatory, but, that is the bad news, it has a negative influence on the pulpal tissues, so today we prefer to use alternatives. Most modern temporary cements are eugenol-free.
Glass-ionomer cements can be seen as also very mild pharmacologic products because of the release of fluoride. The fluoride can be restored, if the oral hygiene is done with a tooth paste containing fluoride in a high concentration – glass ionomer is to be compared with a battery that stores fluoride and can be recharged.
Another cement is mentioned above, the “Ledermix” cement, and must not be discussed again.
The usual cements based on phosphoric acid (zinc phosphate) do not release medical important contents; the effect is just the very low pH (about pH 1 at the beginning of the reaction) that can kill bacteria. At the other hand, the influence of acid can irritate the pulp as well, so it is advised to do the mixing of the cement in a special way (little portions of zinc oxide first, intensive mixing, later more zinc oxide to make the cement less aggressive) – the pH is than not so deep to hurt the pulp. Today it seems better to take just glass ionomer cements for fixation and cementation of crown and bridgeware.
Filling materials
There is a lot of research to improve dental materials, especially filling materials. It is given evidence, that modern composite materials (resin filling material) accumulate more than seven times more dental plaques – a synonym for bacteria – than natural tooth tissue. In contrary, amalgam acquires less plaque, in modern speech “biofilms”. So it is a problem to use resin materials – the risk of secondary caries is high, too high.
Developers all over the world try hard to solve this problem. So there were invited materials with high release of fluoride, other medical substances release against bacteria is not available in the moment.
Most fluoride release is to expect from glass ionomer, second is compomere, and composite is last. This ranking seems to be constant, all other promises up to now did not come true. And, the release of fluoride in both compomere and composite is too low to expect any strong influence on caries related bacteria.
Compomere is in fact just a modified composite – the development began with resin backed glass ionomers and lead to the invention of compomere (by DMG, Germany) and found broad acceptance after manufactured by 3M and actual Dentsply (Dyract). If looked at, we find that the amount of fluoride release is still low, relative to glass inomere, and so you should be careful: leakage of margins cause secondary caries, other as leakage of amalgam fillings.
Endodontics
It is impossible to perform instrumentation of root canal systems so perfect, that there are no bacteria anymore. So it is obvious necessary to use antibacterial substance to reach the aim of bacteria free (or at least just few residing microorganism) canal system. Usually we take antimicrobial rinsing, like hypochlorite or CHX. An common hypochlorite solution is for example “Histolith” (Lege artis), a 5 % sodium hypochlorite solution for ready use.
Peroxides are also commonly in use, but because of possible irritation of apical tissue peroxides are not the best. Handle peroxides with care!
After canal preparation and rinsing we have got no perfect prepared root canal, as one may expect. There is still a mass of bacteria left (at least if we are treating teeth with a necrotic pulp), and so success is not for sure if we try to seal.
So what to do?
The aim is to reduce bacteria – so we need antibacterial stuff. A very common method is to place a paste containing calcium hydroxide inside the root canal and wait some time. Calcium hydroxide is the “gold standard”, but it works very slow. More effective is for example Ledermix paste, the combination of Doxicyclin and stereoid, as mentioned above. Placed in root canal as a temporary filling, it eliminates bacteria and also stops pain very fast because of the anti-inflammatory corticoid influence. Is the patient pain-free, it is to be changed against calciumhydroxide (corticoids inhibit the regeneration of tissue) to enhance the apical bone growth, and in two or three months post op apical lesions are totally eliminated.
But, please, remember: never mix Ledermix paste with Calciumhydroxide! The result will just be inactivation of both. Ledermix works best in low pH, Calciumhydroxide causes a high pH, this can not be good. And, thinl about application. Ledermix paste is thixotroph, that means, the paste will becomme very liquid if compressed. This is helpful when using a lentulo – the paste goes easy to all niches and microcanals, also to the apex, and when you draw the lentulo out, the viscosity is rising fast, so even in upper jaw the paste will remain. Some dentist try to insert Ledermix paste with paper pins – this is ineffective. Think about paper pins – this pins are made to dry the canal system, so they take a lot of water. If you try to transport Ledermix paste with this paper, you just take out water of the paste, and this will cause a very high viscosity – so you will never reach the microcanals ot the apex.
Another way is to place CHX inside the canal. As it is not easy to rinse in a perfect manor, it is possible to place guttapercha points, containing CHX (for example “active point” Coltene/ROEKO, Germany). This is very fast and convenient
Table 1 shows some exemplary material for temporary root filling
Table 1:
Table 1:
Temporary root filling materials
An old method is to place jodoform inside the canal – it is effectice against bacteria and will nor leave microorganismn after use. The bad news in this case is that if a patient suffers with undetected thyroidal adenoma it can result in a hyperthyroid crisis. So one should be careful with this kind of temporary root filling.
Further there is a method described as “iontophoresis”; it works with a electrical potential put onto the tooth, and the electric flow is transporting the contents of temporary root filling material down to apical region and also into the ramifications. Normally there is used calcium hydroxide in combination with copper oxide. Copper has proven as a depot medication that means, the antibacterial influence will last very long. It is to compare with the former method to insert pins of silver inside root canals – silver ions are strong antibacterial.
If the tooth is without any clinical symptoms and also the x-rays show no shadow anymore, it is time for sealing.
Befor sealing, you have to secure perfect cleanliness and also surfaces of root canals that will allow good adhesion of the sealers. For effective cleaning of root canals it is important that the smear layer produced during mechanical root canal preparation (reaming) is removed and that the debris blocking the apertures of dentinal tubules be cleared away, to allow the solution of dressing unobstructed access into the tubules. Hypochlorite does not remove the plugs in the dentinal tubules.
A handy product, TUBULICID PLUS (Dental Therapeutics) however, has the necessary properties: it opens the dental tubules. So it is an effective cleanser and has low surface tension which facilitates penetration of the dentinal tubules. Declarations of contents by the manufatorer:
Cocoamphodiacetate
Benzalkonium Chloride
Disodium Edetate dihydrate
Phosphate Buffer Sol.
Aqua Dest.
Aim of sealing of root canal systems should be that there is no cleft left – and, it should be no influence at local tissues or at least systemic reaction. Nevertheless there are a lot of sealers, and not all are totally neutral.
Prophylaxis
There is a lot of development in prophylaxis – varnishes, liquids and pastes are available by now, and almost daily there is enhancement.
Principles are two: antibacterial and tooth structure hardening substances are distributed, and both can be used alone or in combination. Tooth hardening is the role of fluoride. As we have learnt recently, fluoride dos not have any systemic effect but just tropic. So there is a lot of material containing fluoride in different modifications – fluoride in ionic form, as example sodium fluoride, bound in complex, for example fluoride pyrophosphate, and organic fluoride, as example amino-fluoride (Olafluor/Elmex Fluid, Gaba, Switzerland). Most fluoride has low pH, so be careful by using in mouths with ceramic restorations (the fluoric acid destroys ceramics!) and implants (the titanium that is used for implant posts is also sensible against fluoric acid). In cases with ceramics or titanium it would be better, if fluoride is wanted, to use sodium fluoride that reacts neutral. You can use, for example, “CONTROCAR”(lege artis), a sodium fluoride suspension.
The other sort is the antibacterial content: this can be CHX (Chorhexidin-di-gluconate), like you will find in Cervitec (Ivoclar Vivadent, Schaan/Liechtenstein), or other substances with effect against bacteria, like Triclosan (found in some toothpaste, for example “Colgate Total”).
The pharmaceutical contents out of prophylaxis materials are working also after the paste is rinsed out of the oral cavity – for example, CHX is active about 12 hours post operation.
Antibacterial periodontal local medications
There are gels available with long lasting effect, for example Gels containing Metronidazol or CHX, to be placed inside the periodontal pockets.
You can also use pastes with Doxicyclin (Distributor Riemser, Germany) and bring the paste to the bottom of the pocket – the local therapy often is more effective than the systemic dose (local placement allows a much higher local concentration of the antibiotic than it is possible by blood transportation).
Last but lot least it is to mention the use of retraction help in case of impression. Normally there is a use of aluminachloride or other strong blood coagulation stimulating chemicals (example: Retracto, ROEKO, containing aluminachloridehexahydrate); but, there is also adrenaline in use, that has influence on the organism as well and not just in oral site.
Dr. Gerhard Hetz
München, Germany