Technical field of invention:

The present invention relates a pharmaceutical composition for dental treatment.
The pharmaceutical composition is related to a unique combination of antimicrobials comprising of antibacterial and antifungal agent which are very specific against the pathogenic endodontic micro flora which are exclusively responsible for infections of root canal system.

Prior Art:

Elimination of pathologic endodontic microorganisms and complete removal of infected pulp tissue from the root canal system is the primary objective of root canal therapy. The success of root canal therapy mainly depends on elimination of pathologic micro flora, appropriate bio-mechanical preparation, and complete obturation thereby facilitating fluid tight seal of root canal system. Pathologic endodontic microorganisms and their by-products are considered as one of the major etiological agents responsible for pulp necrosis and peri-radicular lesions. In most cases, failure of root-canal therapy occurs when treatment procedure fails to meet satisfactory standards for destruction and removal of microorganisms. Persisting bacteria and fungi in root canals may be those originally present in the necrotic pulp that survive the endodontic procedures due to anatomic structural complexities and limitations of access by instrumentation and irrigants. In addition to this, pathogenic bacteria present in the oral cavity can contaminate the root canal system during treatment owing to inadequate aseptic control or invade the root canal system via coronal leakage after rootcanal treatment.

Enterococcus faecalis, Candida albicans and their various strains are most commonly found pathogenic microorganisms in the root canals of the teeth with failed endodontic treatment. Root canal treated teeth are about nine times more likely to harbor Enterococcus faecalis and Candida albicans than untreated cases of primary infection and hence they are the most commonly isolated species of microorganism in failed root canal treated teeth.

Other than E. faecalis and C. albicans there are a host of other microorganisms like Porphyromonas, Prevotella, Fusobacterium, Tannerella, Dialister, Campylobacter, Treponema, Peptostreptococcus, Parvimonas, Eubacterium, Filifactor, Actinomyces, Propionibacterium and Pseudoramibacter, facultative or microaerophilic Streptococci, Black-pigmented bacteria (BPB) lactobacilli, Actinomyces species, Peptostreptococci, Pseudoramibacter alactolyticus, Propionibacterium propionicum, Dialister pneumosintes, and Filifactor alocis that are frequently isolated from teeth with pulpal infection/ disorder (primary & secondary).

The use of antibiotics for endodontic were first reported in 1951 which was known as polyantibiotic paste (PBSC). PBSC consisted of penicillin, bacitracin, and streptomycin and caprylate sodium. Penicillin was used for targeting against Grampositive organisms, bacitracin for penicillin-resistant strains, streptomycin for Gramnegative organisms and caprylate sodium to target yeasts.

Triple Antibiotic Paste (TAP) of various combinations has been used in the past as an intra canal medicament for disinfecting the root canals of teeth prior to endodontic therapy. But endodontic therapy after the use of TAP has shown varying success rate. However, use of TAP is a cause of concern as the dosage of the different drug varies with no standardization of the components and often leads to certain side effects including chronic inflammation of the adjoining periradicular tissue. The choice of antimicrobial agents is neither justified nor has the combination been rationalized against the specific pathogenic micro flora of root canal system. For e.g. Ciprofloxacin (1st generation FQ) used in TAP has antimicrobial activity against most Gram – negative bacilli and cocci, but limited activity against most gram positive organisms. Use of TAP is also undesirable by clinician and researchers as it leads to severe discoloration of the teeth in almost all the cases. Another disadvantage of TAP is the absence of standard delivery method and protocol. The preparation of the TAP is need to be done immediately before placement, just before use, which is a time consuming procedure and also is done in an unsterilized manner. The particle size of the powder, obtained after mixing crushed antibiotic tablets in mortar and pestle is large and also uneven which restricts its entry into the fine and torturous dentinal tubules. Hence the micro-organism residing inside the dentinal tubules usually escapes out. There is no justification for the choice of antibiotics, except all of them have a broad spectrum of bacteriostatic action. TAP does not incorporate any antifungal agent which makes it ineffective against Candida albicans.

Objective of the invention

The primary object of the present invention is a pharmaceutical composition for dental treatment.

Summary of the invention:

Accordingly following invention is a pharmaceutical composition for dental treatment.

According to an embodiment, the pharmaceutical composition is related to a unique combination of antimicrobials comprising of antibacterial and antifungal agent which are very specific against the pathogenic endodontic micro flora which are exclusively responsible for infections of root canal system.

According to an embodiment the quantity administered each time during the treatment cannot be determined as it depends on the volume of the root canal system. It varies in each tooth as the volume of the root canal system of the teeth varies in individual tooth. However, it may range from 0.6 – 0.9 ml. The effects of the formulation were seen immediately after insertion, which was assessed after 24 hours and also it remained effective for 14 days.

Detailed description of invention:

The following description includes the preferred best mode of one embodiment of the present invention. It will be clear from this description of the invention that the invention is not limited to these illustrated embodiments but that the invention also includes a variety of modifications and embodiments thereto. Therefore, the present description should be seen as illustrative and not limiting. While the invention is susceptible to various modifications and alternative constructions, it should be understood, that there is no intention to limit the invention to the specific form disclosed, but, on the contrary, the invention is to cover all modifications, alternative constructions, and equivalents falling within the spirit and scope of the invention as defined in the claims.

In any embodiment described herein, the open-ended terms "comprising," "comprises,” and the like (which are synonymous with "including," "having” and "characterized by") may be replaced by the respective partially closed phrases "consisting essentially of," consists essentially of," and the like or the respective closed phrases "consisting of," "consists of, the like.

The present invention is a pharmaceutical composition for dental treatment.
It is related to a unique combination of antimicrobials comprising of antibacterial and antifungal agent which are very specific against the pathogenic endodontic micro flora which are exclusively responsible for infections of root canal system. Various literatures were reviewed to find out all the micro – organisms (micro flora) which were specifically responsible for primary infection of untreated cases and endodontic treatment failures. After the completion of search, it was found that the most frequently detected culturable species in primary infection belong to the Gram-negative genera Porphyromonas, Prevotella, Fusobacterium, Tannerella, Dialister, Campylobacter and Treponema. Gram-positive anaerobes from the genera Peptostreptococcus, Parvimonas, Eubacterium, Filifactor, Actinomyces, Propionibacterium and Pseudoramibacter, as well as facultative or microaerophilic Streptococci can also be commonly found in primary infection. Black-pigmented bacteria (BPB) are the species that are also frequently been isolated. It was found that the E. faecalis and C. albicans were responsible for of failure of root canal therapy as well a host of many other organisms also such as Lactobacilli, Actinomyces species, Peptostreptococci, Pseudoramibacter alactolyticus, Propionibacterium propionicum, Dialister pneumosintes, and Filifactor alocis also caused failure of root canal therapy.

The access to infected pulp of the teeth is gained by drilling the tooth and pulp tissue is completely removed from the chamber and the root canals, the root canal and pulp chamber is filled with the below mentioned pharmaceutical composition under aseptic condition. Drugs Chemical Formula For 10 ml solution Trovafloxacin mesylate (0.15mg) C20H15F3N4O3.CH3SO4H 0.8ml (8%) Doxycycline Hydrochloride (0.6 mg) C22H25ClN2O8 3.2ml (32 %) Nystatin (0.3mg) C47H75NO17 0.9ml (9%) Chitosan Hydrochloride (100mg) Hydroxy Propyl Methylcellulose (300mg) C56H103N9O39 C56H108O30 4.8ml (48%) Sodium ß Glycerophosphate pentahydrate (98%) Na2C3H5(OH)2PO4. 5H2O 15ml (15%) Benzalkonium Chloride C17H30ClN 0.006 ml (0.06 %) Potassium Iodide (8M) KI 0.290 ml (2.90 %)

The pharmaceutical composition is prepared using the following components: Trovafloxacin is a 4th generation Fluoroquinolone with extended spectrum of activity, including anaerobes and Gram positive organisms, especially the multiresistant ones. Trovafloxacin is one of the most active antibiotic against E. faecalis. In addition to antimicrobial activity studies, the pharmacokinetic and pharmacodynamic properties of Trovafloxacin have been studied, and have showed excellent bioavailability, long plasma halflife and good tissue penetration. Furthermore, it has an excellent tolerability. Studies by several authors have shown that Trovafloxacin has good antibacterial activity against periodontal pathogens and bacteria isolated from dentoalveolar abscesses. The latter have suggested the potential use of Trovafloxacin in the treatment of odontogenic infections. Studies also revealed that Trovafloxacin had good in vitro activity against E. faecalis isolates from the root canals and seems to be a reasonable alternative for patients who are allergic to penicillin or show resistance to the antibiotics.

Tetracyclines, including tetracycline-HCl, minocycline and doxycycline, are a group of broad-spectrum bacteriostatic antibiotics with activity against aerobic and anaerobic Gram-positive and Gram-negative organisms. This property is advantageous because, in the absence of bacterial cell lysis, antigenic by-products such as endotoxin are not released. Tetracyclines also have many unique properties other than their antimicrobial action, such as the inhibition of mammalian collagenases, which prevent tissue breakdown and the inhibition of clastic cells, which results in antiresorptive activity. In endodontics, tetracyclines have been used to remove the smear layer from instrumented root canal walls, irrigation of retrograde cavities during periapical surgical procedures, and as an intracanal medicament. The effect of doxycycline-HCl was evaluated on the smear layer of instrumented root canal walls. It was evaluated that the effect of doxycycline on the apical penetration of dye through the margins of retrograde fillings. The teeth with retrograde IRM or amalgam fillings placed subsequent to doxycycline irrigation had significantly less dye penetration than those that were not irrigated with doxycycline. Carson et al. used an agar diffusion test to compare the antimicrobial activities of 6% and 3% sodium hypochlorite (NaOCl) solutions, 2% and 0.12% chlorhexidine gluconate (CHX), and 0.01% and 0.005% doxycycline (Doxy) on four microorganisms associated with endodontic infections of teeth that had not been previously treated, namely Peptostreptococcus micros, Prevotella intermedia, Streptococcus sanguis, and Lactobacillus acidophilus. For the first three of these organisms, the general order of antimicrobial effectiveness was 0.02% Doxy >0.006 Doxy >6.5% NaOCl >3.3% NaOCl >2.5% CHX > 0.14% CHX. However, for L. acidophilus, the order of effectiveness was 5% NaOCl >4% NaOCl >2.5% CHX > 0.02% Doxy >0.006 Doxy >0.16% CHX. Pinheiro et al. evaluated the antibiotic susceptibility of Enterococcus faecalis isolates from canals of root-filled teeth with periapical lesions. The antibiotics were benzylpenicillin, amoxicillin, amoxicillin with clavulanic acid, erythromycin, azithromycin, vancomycin, chloramphenicol, tetracycline, doxycycline, ciprofloxacin and Trovafloxacin. The vast majority (87.5%) of the isolates were susceptible to tetracycline and doxycycline. Tetracyclines readily attach to dentine and are subsequently released without losing their antibacterial activity. This property creates a reservoir of active antibacterial agent, which is then released from the dentine surface in a slow and sustained manner. Doxycline hydrocloride treatment seemed to give a less negative effect on osteoblasts. Consequently, it might be assumed that it could enable more regenerative healing of tissues.

Penicillins are the most frequently used antimicrobial agents. Due to their historical effectiveness, minimal toxicity and relatively low cost, penicillins constitute the first-choice antibiotics for odontogenic infections. Important classes of penicillins include penicillins G and V, which are highly active against susceptible Gram positive cocci, and amoxicillin with an improved Gram negative spectrum. All strains studied were susceptible to penicillins in vitro, however, the MICs of amoxicillin and amoxicillin-clavulanic acids were lower than for benzylpenicillin. It was also found that enterococci are more sensitive to amoxicillin than to benzylpenicillin. All E. faecalis strains isolated from canals of root filled teeth with periapical lesions remain 100% susceptible, in vitro, to amoxicillin.

Nystatin is a polyene antibiotic, obtained from S. noursei and is highly active against C. albicans and other fungi and is preferred over other antifungal agents for local applications. Resistance to Nystatin has been rarely noted among candida and is not a problem in the clinical use of drugs.

Chitosan is a natural polycationic copolymer consisting of glucosamine and N-acetyl glucosamine units. It is mostly obtained by deacetylation of chitin derived from the exoskeleton of crustaceans. Chitosan has valuable properties as biomaterials because it is considered to be biocompatible, biodegradable and nontoxic. The cationic character and the potential functional group make it an attractive biopolymer for many biomedical and pharmaceutical applications. As a pharmaceutical excipient, chitosan has been used in many formulations like powders, tablets, emulsions and gels. Furthermore a controlled release of incorporated drugs can be guaranteed. Chitosan also shows mucoadhesive and antimicrobial properties. The amino group in chitosan has a pKa value of ~6.5, which leads to a protonation in acidic to neutral solution with a charge density dependent on pH and the %DA-value. This makes chitosan water-soluble and a bio-adhesive which readily binds to negatively charged surfaces such as mucosal membranes. Chitosan enhances the transport of polar drugs across epithelial surfaces. Chitosan’s properties also allow it to rapidly clot blood. The hemostatic agent works by an interaction between the cell membrane of erythrocytes (negative charge) and the protonated chitosan (positive charge) leading to involvement of platelets and rapid thrombus formation. Utilization of Chitosan as vehicle enables the maximum availability of drugs at the site of action. Chitosan has a positive charge under acidic conditions (acidic condition is encountered due the presence of pathogenic microorganism in primary and secondary root canal infection). This positive charge comes from protonation of its free amino groups. Lack of a positive charge means chitosan is insoluble in neutral and basic environments. However, in acidic environments, protonation of the amino groups leads to an increase in solubility. This molecule solubilizes and degrades early in an acidic than in neutral and alkaline environment. This means chitosan effectively facilitates the maximum availability (but in controlled manner) of drugs in the required infected acidic environment.

Hydro-oxy propyl methyl cellulose is an inert viscoelastic polymer used as an emulsifier, thickening and suspending agent similar to animal gelatin. It is used in the development of controlled-delivery medicament. It is a solid, and is a slightly off white to beige powder in appearance and may be formed into granules. The compound forms colloids when dissolved in water. In an aqueous solution, unlike methylcellulose, it exhibits a thermal gelation property. That is, when the solution heats up to a critical temperature, the solution congeals into a non-flowable but semi-flexible mass. Due to the conversion of the formulation in semi-soluble mass it does not quickly diffuses out of the root canal system but retains there and essentially releases the drug over a longer period of time.

Benzalkonium chloride is used as a preservative and also a potential antimicrobial agent. It conveniently imparts the present invention longer shelf life, which helps to store it for 12 months without any change in its physical properties.

Potassium Iodide is used as a radio opaque substance and imparts it the ability to be visible on x- ray or Radio- Visio Graphy (RVG).

Sodium ß Glycerophosphate pentahydrate is used in the development of hydrogels and scaffolds that have applications in tissue engineering and cell growth and differentiation. Beta-Glycerophosphate is a classical serine-threonine phosphatase inhibitor used in kinase reaction buffers. BGP is often used in combination with other phosphatase/protease inhibitors for broad spectrum inhibition. It functions as an organic phosphate donor and has been used for mesenchymal stem cell differentiation to osteoblast-type cells.

The process for preparing the antimicrobial composition is as follows:
Chitosan Hydrochloride, Hydroxy Propyl Methylcellulose are soaked in few ml of deionized water maintained at 4? C for 24 hours. To the resulting solution Trovafloxacin mesylate, Doxycycline Hydrochloride, Nystatin are added and stirred to make a homogenous mixture. Temperature is maintained below 10? C throughout the formulation. After that few ml of 0.282 M Sodium ß Glycerophosphate pentahydrate is added drop by drop with continuous stirring. 0.300 ml, 8M potassium iodide and 0.05% Benzalkonium chloride were added thereafter and the pH is adjusted to 7.0 using 1M NaOH. A final volume of 10ml is achieved using deionized water. The effective combination of anti-microbial agent in solvent has improved wettability, which is able to diffuse deep into the dentinal tubules of root canal system.

The percentage of the Antibacterial agents (Trovafloxacin mesylate, Doxycycline Hydrochloride) and antifungal agent Nystatin could not be decreased as it is as per the Minimum Inhibitory Concentration (MIC) any concentration below this will have no inhibitory action on the microorganism.

The percentage of Trovafloxacin mesylate can be increased upto 4 times its present concentration. The increase in concentration can be upto it’s MBC (Minimum bactericidal concentration) which is about four times it’s MIC concentration The percentage should not be increased beyond MBC an it is not advisable as it will hamper the basic idea behind the preparation of this formulation which is the rationalized used of drugs and the concentration which in range between MIC and MBC. Also an increase in concentration of Doxycycline Hydrochloride may cause discoloration of tooth.

The quantity administered each time during the treatment cannot be determined as it depends on the volume of the root canal system. It varies in each tooth as the volume of the root canal system of the teeth varies in individual tooth. However, grossly it may range from 0.6 – 0.9 ml. The effects of the formulation were seen immediately after insertion, which was assessed after 24 hours and also it remained effective for 14 days.

Additional advantages and modification will readily occur to those skilled in art. Therefore, the invention in its broader aspect is not limited to specific details and representative embodiments shown and described herein. Accordingly various modifications may be made without departing from the spirit or scope of the general invention concept as defined by the appended claims and their equivalents.

While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention.

Claims:

1. This invention analyzes a pharmaceutical composition for dental treatment.
2. According to an embodiment the quantity administered each time during the treatment cannot be determined as it depends on the volume of the root canal system.
3. According to an embodiment the quantity administered may range from 0.6 – 0.9 ml. The effects of the formulation were seen immediately after insertion, which was assessed after 24 hours and also it remained effective for 14 days.