Title of Invention

BIODEGRADABLE POLYMERIC MONOLITHIC FILM USEFUL FOR THE RESTORATION OF THE PERIODONTIUM

Abstract

This invention discloses a biodegradable polymeric monolithic film useful for the restoration of peridontium which comprises a glass film lined with aluminium foil, the aluminium foil having a coating of biodegradable polymer in an organic solvent containing an active agent (drug). This invention also discloses a process for the preparation of the above defined biodegradable polymeric monolithic film.

Full Text

BACKGROUND OF THE INVENTION This invention relates to biodegradable polymeric monolithic Him. The biodegradable polymeric monolithic film of the prescnr invention is useful for the restoration of the periodontium Present state of the art Dental diseases are among the most widespread chronic disorders affecting mankind. Epidemiological studies carried out in many parts of the world have documented the high incidence of caries and periodontal diseases. Compared to the widespread use of drugs for treating many medical conditions, relatively little use has been made of such forms of therapies in dental settings. Although employed to allay pain and anxiety, and with the exception of fluoride, drugs have been rarely used for treating dental diseases. The reasons behind this apparent omission are of interest in the context of controlled delivery approaches. The effectiveness of drugs in dental diseases has generally been evaluated only for conventional delivery modes. Dental diseases can often be traced to body compartments adjoining, but outside, the mucosal layer. Systemic administration of drugs for treating these diseases may be effective for pathogenic processes that have "crossed" the mucosal barrier. However, if the disease remains outside the range of the host's defense system, systemic therapy simply uses the body as an inefficient conduit for drug delivery, diluting the agent several thousand fold before it reaches the site of infection. Periodontal disease can be defined as an infection and inflammation of the gingiva or gums that could lead to loss of underlying alveolar bone support. There are varying levels of severity of the disease. The mildest cases are clinically termed gingivitis (inflamed and bleeding gums). More severe cases are clinically known as periodontitis and can involve loss of bone support. Gingivitis is reversible and can often be eliminated with a thorough dental prophylaxis followed by improved personal oral hygiene procedures. If gingivitis is not ■ s ■ controlled, the disease often progresses into periodontitis. Periodontitis is characterized by bacterial infection and inflammation and accompanied by the formation of periodontal pockets (spaces between the teeth and gums) and bone destruction, which could lead to tooth loss. Periodontitis is progressive, episodic and recun*ing. In the course of periodontal disease, the infection of gingival tissue by plaque bacteria causes the ligaments attaching the gum and teeth to recede, decalcifies the bony structure holding the teeth roots to the bone, and forms periodontal pockets in the gingival tissue adjacent the teeth. Successful periodontal restoration is known to occur if pcriodonlal ligament cells are allowed to colonize root surfaces preferentially over gingival epithelial cells, gingival fibroblasts or osteoblasts. Effective management of periodontitis is lo apply professional intervention to halt disease progression. Professional intervention ma^ involve surgical or nonsurgical procedures. Nonsurgical treatment consists of periodic professional scaling and root planing, in combination with conscientious home care by brushing and flossing on the part of the patient. Surgical treatment involves curettage, gingivcctomy and (lap surgery to recontour the soft and hard tissue around the diseased areas. In recent years, it has become increasingly recognized that control of pcrio, donlitis may be possible with the use of antimicrobial agents delivered to the infected site. Systemic antibiotics taken orally or intramuscularly have been successfully usedbut due to the concern about allergic responses, the development of resistance, very low concentrations of antibiotic delivered to the diseased site and the treatment of the whole person rather than the specific infected site, their use is recommended only in the more severe forms of periodontal diseases. Treatment by mouth rinse and other topically applied oral drugs does not allow the antibacterial agents to penetrate into the periodontal pocket where they are needed. Irrigation of the pockets with these agents has shown some effects on gingivitis, however the short time of exposure with irrigation solutions and the rapid removal of the therapeutic agent by the outward flow of the crevicular fluid make this type of treatment ineffective in severe periodontitis. There are a few problems that must be solved to treat the periodontitis by a local drug delivery system. First, a carrier is necessary to transport a physiologically active substance such as antibiotics to the periodontal pocket. A large number of carriers developed so far are substances that are no.t^absorbed biologically, which must be removed after the drug is released completely and if not, they irritate the periodontal tissue and inhibit the regeneration of the periodontal tissue. This problem could be solved by the use of biodegradable polymers, which degrades to yield biocompatible monomers that are metabolized and eliminated from the body. Biodegradable polymers thus obviate the need to remove the drug depleted delivery device. Second, to treat the periodontitis, effective concentration of^thc active substance in the periodontal pocket must be maintained for a long time. It was observed that the therapeutic agent should be retained at the affected site as long as possible because dental diseases are generally chronic. It is reported that an effective concentration of antibiotics such as minocycline hydrochloride must be maintained for at least 7 to 10 days to treat the periodontitis. Third, it is needed that the process of administration is convenient and quantitative on the basis of the amount of active substance delivered to the site. ■ To the best of our knowledge a system meeting all the above mentioned requirements are not available. It is our intension provide a system meeting all the above mentioned requirements. Objectives of the invention Therefore it is the main objective of the present invention to provide a biodegradable polymeric monolithic film useful for the restoration of the periodontium which is safe, quick easy and eflficient It is another objective of the present invention to provide a biodegradable polymeric monolithic film useful for the restoration of the periodontium which contains an active agent (drug). Yet another objective of the present invention to provide a biodegradable polymeric monolithic film useful for the restoration of the periodontium which retains the effective concentration of the active substance (drug) in the periodontal pocket for a long time say for a period in the range of 60 to 90 hours Still another objective of the present invention to provide a biodegradable polymeric monolithic film useful for the restoration of the periodontium which is convenient and quantitative on the basis of the amount of active substance ( drug) to be delivered at the site. Further objective of the present invention lo provide a process for the preparation of the above mentioned film for the restoration of the periodontium. AcGurQlingly the present invention provides a biodegradable polymeric monolithic film useful for the restoration of the periodontium which comprises a glass film lined with aluminium foil, the aluminium foil having a coating of a solution of a biodegradable polymer in an organic solvent containing an active agent ( drug). ^rhe biodegradable polymeric monolithic film of the present invention can be used to aid in the restoration of the periodontium by the delivery of the active agent ( drug) to restore the periodontium. The biodegradable polymers which can be used are those, which have lower degree of crystallization and are more hydrophobic. Preferred materials with the desired solubility parameters are the polylactides, polycaprolactoncs, and copolymers of these with each .other and glycolide in which there are more amorphous regions to enhance solubility. More preferable biodegradable polymer, which can be used -according to the present invention is poly (6-caprolactone). The biodegradable polymeric monolithic film of the present invention is obtained by solvent casting method by dissolving the biodegradable polymer in an organic solvent containing the active agent (drug) and casting over a glass film lined with aluminum foil. The polymeric monolithic film can be retained at the site of implantation for a prolonged period of time say 60 to 90 days by the incoiporation of an muco adhesive agent such as carbopol 934 P, Hydroxypropyl cellulose, HPMC K4M, Chitosan, Guar gum, Xanthan gum and the like. The muco adhesive agent which is present is dispersed in the polymer solution by sonication. The solvent which can be used may be selected from methylene chloride, chloroform, acetone, acetonitrile, isopropyl alcohol. The tcnn drug or bioactive (biologically active) agent as used herein includes without limitation physiologically or pharmacologically active substances that act locally or systemically at a periodontal site. Drug used with the biodegradable film may preferably be doxycycline hyclate. To those skilled in the art, other drugs or biologically active agents that can be released in an aqueous environment can be utilized in the described delivery system. The amount of drug or biologically active agent incorporated into the solid implant depends upon the desired release profile, the concentration of drug required for a biological effect, and the length of time that the drug has to be released for treatment. There is no critical upper limit on the amount of drug incorporated into the polymer solution except for that of an acceptable solution or dispersion viscosity. The lower limit of drug incorporated into the delivery system is dependent simply upon the activity of the drug and the length of time needed for treatment. In the present invention, 1:20 drug :polymer ratio was used to obtain the desired release characteristics for a period of 60 days. Not only can the drug incorporated into the system be used to create a biological effect, but it can also be used to create the microporous structure needed for connective tissue ingrowth and barrier to epithelial migration. If the drugs is highly water soluble, it will be dissolved or released from the polymer matrix quickly and create the pores required lor tissue ingrowth.-If the drug is released or dissolved slowly, the pores can be created at a rate similar to that for cell migration into the newly formed pores. The size of the pores will be dependent upon the size of the drug particles in the polymer malrix. IT the drug is insoluble in the polymer formulation, then discrete particles of drug can be properly sized or sieved before incorporation into the polymer solution to give the diisired pop size. If the drug is also soluble in the polymer solution, then the distribution or mixing of the drug within the fonnulation and the method by which the drug precipitates upon contact with water of body fluids will determine the pore sizes when the precipitated particles are later dissolved. The pore sizes can be determined by examining cross-sections of the coagulated polymer matrix with scanning electron microscopy. According to another feature of the present invention there is provided a process for the preparation of biodegradable polymeric monolithic film useful for the restoration of the periodontium which comprises dissolving the biodegradable polymer in an organic solvent containing the active agent ( drug) and casting over a glass sheet having a lining of aluminium foil. Before use, the film of the biodegradable polymer containing the active agent ( drug) is peeled off from the glass film. Once in place, the film swells and the mucoadhesive agent aids in retaining the film at the site. The polymer will adhere to the surrounding tissue or bone by mechanical forces. The solvent evaporates leaving behind a unilbrm monolithic film. The film is then cut into pieces of 0.5 x 0.5 cm. The release of the drug from these solid implants will follow the same general rules for the release of a drug from a monolithic polymeric device. The release of the drug can be affected by the size and shape of the implant, the loading of drug within the implant, the permeability factors involving the drug and the particular polymer, the porosity of the polymer implant or membrane, and the degradation of the polymer. The biodegradable film slowly biodegradcs within the periodontal site and allows the natural tissue to grow and replace the implant as it disappears. Thus, when the film is implanted into a soft-tissue defect, it will fill that defect and provide a scaffold for natural collagen tissue to grow. In the case of the film used for the administration of a drug the solid microporous film containing the drug when administered will release the drug contained within the film at a controlled rate until the drug is depleted. The details of the Invention arc described in the Examples given below which are provided only to illustrate the invention and therefore ihcy should not be construed to limit the scope of the invention EXAMIM.E 1 ■^ Ciprofloxacin- p- cyclodextrin complex 265 mg (^'to 60 mg cipronoxacin) Tinidazolc 60 mg Carbopol 934P NF 180 mg Poly ( e - caprolactone) 1 -2 mg Dichloromethane 8.0 ml Poly ( e - caprolactone) (molecular weight 72,000) (1.2 g) was dissolved in 8.0 ml of dichloromethane. To this carbopol 934P NT (180 mg) and Ciprofloxacin- P- cyclodextrin complex ( 265 mg) along with Tinidazolc (60 mg) were dispersed in polymer solution. The dipersion is then sonicated for uniformity, poured in a glass mould (5.0 cm x 3.0 cm)lined with aluminium foil and allowed to dry, 1 he dried film is then cut into 0.5 cmx 0.5 cm films. Each film contained 1 mg of the drug EXAMPLE 2 Doxycycline hyclate 60 mg Carbopol 934P NF 180 mg Poly ( e - caprolactone) 1.2 mg Dichloromathane 8.0 ml Poly (s-caprolactone) (1.2 g) is dissolved in methylene chloride (8 ml). Carbopol 934 P was (180 mg) was dispersed in the resulting polymeric solution. Doxycycline hyclate (60 mg) was dissolved in the polymeric solution and the film is casted on the aluminium lined glass mould and vaccum dried. In vitro drug release studies was conducted of the film obtained by the process described in EXAMPLE 2 by vial method for a period of 60 days. The drug was released in a biphasic manner with an initial burst release for the first 24 hours followed by sustained release for a total period of 1440 hours (60 days) as shown in I'igure 1. Figure 1. In vitro release profile of doxyoycline hyclate from poly (E-caprolactone) films In vivo studies was conducted of the film obtained by the process described in EXAMPLE 2 in the patients visiting to Department of Pch-iodontics, College of Dental Surgery, KMC, MAHE, Manipal. Kasturba Hospital Ethical Committee approved the protocol of the study. Results indicated a significant improvement in the cHnical parameters such as plaque index, gingival index, reduction in the probing depth and gain in the attachment level after 60 days as shown in the Table 1 below. Gingival crevicular fluid and saliva concentration of the drug was found to be above the minimum inhibitory concentration for pcriodontopathic bacteria as shown in Figure 2. Figure 2. Concentration of doxycyclinc hyclate in GCF and saliva after treatment with Poly (e-caprolactone) films Films containing doxycyclinc hyclate released 32.07 %, 73.98 % and 89.97% of drug at the end of 24 h., 720 h., 1440 h. The drug candidates was released in a biphasic manner characterized by initial burst release followed by a slow release for a prolonged period of time. The burst release in the initial stages could be attributed to the drug present at the surface of the device. During the solvent evaporation process of manufacturing of the device, the drug migrates towards the surface of the device (Huang and Brazel, 2001), which would be available immediately for release into the surroundings. The second phase of slow release of drugs occur by diffusion through the pores formed due to diffusion of water in the polymer matrix and erosion of polymer. Diffusion through a pre- existing pore network in the devices and subsequent enhanced diffusion via erosion induced pore enlargement and evolution could be regarded as a predominant drug release mechanism. Secondary slow release of the drug can be explained by a permeability reduction due to changes in the morphology of the polymer and aUcrnately, a reduction in the concentration gradient across the polymer wall produced by declined rate' of drug dissolution in the polymer. Morphology is potential relevant to the constancy of the release rate because Poly (e - caprolactone) is a semicrystalline polymer subject to slow hydi;olysis /// vitro and in vivo. The resulting molecular weight decrease, coupled with annealing, is associated with a considerable increase in crystallinity, which, in turn, reduces the polymer permeability. Initial burst release of the drug could be favorable particularly in the treatment of periodontitis so as to provide an increased amount of the drug to eradicate the pathogenic microbial flora followed by a slow release to prevent the recolonization and rehabilitation of pathogens. Concentration of doxycycline hyclate in GCV and saliva after treatment with films is depicted in the above figure. GCF concentration of doxycycline hycate after implantation of Poly ( e -caprolactone) films was 5.42± 1.18 Hg/mg after one hour and showed a peak concentration of 6.31± 1.49 |xg/mg at 2"^^ hour. Thereafter, the concentration declined gradually to 3.60 ± 1.08 (ig/mg at the end of 1440 h. (60 days). Salivary concentration of doxycycline hyclate at 1'^ hour was 1.36± 0.78 ^g/mg that declined gradually to 0.8U 0.52 |ig/mg after 1440 hour (60 days). It can be observed that salivary concentration of doxycycline hyclate was less compared to GCF concentration at all lime points. The results indicate that the concentration of doxycycline hyclate achieved in GCF' could elicit the antibacterial effect. Clinical parameters evaluated in patients prior to treatment and after treatment with films containing doxycycline hyclate is summarized in Table 1. It can be observed that there was a highly significant improvement in plaque index, gingival index, probing depth and gain in attachment level (P Advantages of the invention Tlie biodegradable polymeric monolithic film is useful for the restoration of the periodontium which is safe, quick, easy and efficient. The biodegradable polymeric monolithic film retains the effective concentration of drug in the periodontal pocket for a long time, say for a period in the range of 60 to 90 days. The biodegradable polymeric monolithic film is convenient and quantitative on the basis of the amount of active substance (drug) to be delivered at the site. We claim 1. A biodegradable polymeric monolithic film containing doxycycline hyclate, which is prepared by using bioadhesive polymer and organic solvent and is mainly used for the restoration of periodontium, a periodontal disease. 2. A biodegradable polymeric monolithic film as claimed in claim 1 wherein the biodegradable polymer used is selected from the class of polylactides, polycaprolactones, and copolymers of these with each other and glycolide. 3. A biodegradable polymeric monolithic film is claimed in claims 1 and 2 wherein the biodegradable polymer used is Poly (e - caprolactone) 4. A biodegradable polymeric monolithic film as claimed in claims 1 to 3 wherein the solvent used is selected from methylene chloride, chloroform, acetone, acetonitrile and isopropylalcohol. 5. A biodegradable polymeric monolithic film as claimed in claims 1 to 3 wherein active agent (drug) used is selected from ciprofloxacin hydrochloride, titudazole, doxycycline hyclate, sparfloxacin, levofloxacin and ofloxacin. 6. A biodegradable polymeric monolithic film as claimed in claims 1 to 5 wherein the bioadhesive polymer used is Carbopol 934P NF. 7. A biodegradable polymeric monolithic film as claimed in claims 1 to 6 wherein the ratio of polymer and the active agent (drug) used is 1:20. 8. A process for the preparation of biodegradable polymeric monolithic film useful for the restoration of the periodontixmi which comprises following steps: a. Dissolving the drug in an organic solvent b. Dissolving the biodegradable polymer in above solution c. Dissolving or dispersing Carbopol 934? NF in the above resulted solution d. Pouring this mixture over a glass sheet having a lining of alimiinium foil e. After 24 hours the vacuum dried biodegradable polymeric film will be peeled out from the alimiinum foil. 9. A process as claimed in claim 8 wherein the biodegradable polymer used is selected from the class of polylactides, polycaprolactones, and copolymers of these with each other and glycolide. 10. A process for the preparation of biodegradable polymeric monolithic film as claimed in claims 8 and 9 wherein the biodegradable polymer used is Poly (g - caprolactone). 11. A process for the preparation of biodegradable polymeric monolithic fihn as claimed in claims 8 to 10 wherein the solvent used is selected from methylene chloride, chloroform, acetone, acetonitrile, isopropylalcohol. 12. A process for the preparation of a biodegradable polymeric monolithic film as claimed in claims 8 to 11 wherein active agent (drug) used is selected from ciprofloxacin hydrochloride, tinidazole, doxycycline hyclate, sparfloxacin, levofloxacin and ofloxacin. 13. A process for the preparation of a biodegradable polymeric monolithic film as claimed in claims 8 to 12 wherein the bioadhesive polymer used is Carbopol 934P NF. 14. A process for the preparation of a biodegradable polymeric monolithic film as claimed in claims 8 to 13 wherein the ratio of the polymer and the active agent (drug) used is 1:20 15. A process for the preparation of biodegradable polymeric monolithic film as claimed in claims 8 to 14 wherein the solvent used is selected from methylene chloride, chloroform, acetone, acetonitrile, isopropylalcohol. 16. A biodegradable polymeric monolithic film substantially as herein described with reference to the examples. 17. A process for the preparation of biodegradable polymeric monolithic film substantially as herein described with reference to the examples.

Documents:

0004-che-2004 abstract duplicate.pdf

0004-che-2004 claims duplicate.pdf

0004-che-2004 description (complete) duplicate.pdf

004-che-2004-abstract.pdf

004-che-2004-claims.pdf

004-che-2004-correspondnece-others.pdf

004-che-2004-correspondnece-po.pdf

004-che-2004-description(complete).pdf

004-che-2004-drawings.pdf

004-che-2004-form 1.pdf

004-che-2004-form 19.pdf