Title of Invention

BIODEGRADABLE POLYMERIC COMPOSITION USEFUL IN THE TREATMENT OF PERIODONTITIS

Abstract

The invention disclosed in this application relates to a composition in the form of a gel which is useful for the treatment of periodontal disease, which comprises: (a) a water-insoluble biodegradable polymer (b) a biocompatible organic solvent (c) an active agent (drug) and (d) a co-solvent capable of solubilizing the active agent (drug). The invention also relates to a process for the preparation of the above mentioned composition.

Full Text

BACKGROUND OF THE INVENTION This invention relates to biodegradable polymeric composition. The biodegradable polymeric composition of the present invention is useful as a sustained release drug delivery system for the treatment of periodontitis. The biodegradable polymeric composition of the present invention is in the form of gel. Present status 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 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 recurring. 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 periodontal ligament cells are allowed to colonize root surfaces preferentially over gingival epithelial cells, gingival fibroblasts or osteoblasts. Effective management of periodontitis is to apply professional intervention to halt disease progression. Professional intervention may 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, gingivectomy and flap surgery to recontour the soft and hard tissue around the diseased areas. In recent years, it has become increasingly recognized that control of periodontitis may be possible with the use of antimicrobial agents delivered to the infected site. Systemic antibiotics taken orally or intramuscularly have been successfully used, but 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. The term "System" used herein means a composition or a formulation. The system is normally in a lipid form which when applied at the desired site i.e a periodontal pocket, solidifies to form a solid mass from which the drug is released slowly and continuously. 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 not 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. By way of examples of such substances the following are mentioned: - Ethyl cellulose, Methyl cellulose, Hydroxylpropyl cellulose, Eudragits, Hydroxypropyl methyl cellulose, silicon derivatives etc 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 the 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. While the use of bioabsorbable delivery devices represents a major step forward in the treatment of periodontal disease, there remains a need in the art for a composition or formulation which can be easily and more quickly and easily prepared and placed in the periodontal pocket, the infected site, that conform more exactly to the size and shape of each individual pocket for the release of the active agent ( drug) which later solidifies into a hard matrix containing the drug. The drug is released from the matrix slowly and in a sustained fashion. In the present day context the treatment of periodontal disease has gained importance due to the appearance of large number of patients . Therefore there is an urgent need to provide a safe , quick ,easy and efficient system for the treatment of such an important disease Objectives of the invention Therefore it is the main objective of the present invention to provide a composition useful for the treatment periodontal disease which is safe, quick, easy to prepare and efficient Still another objective of the present invention is to provide a composition useful for the treatment periodontal disease which employs an active agent (drug) Yet another objective of the present invention to provide a composition useful for the treatment periodontal disease 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 days. Still another objective of the present invention to provide a composition useful for the treatment periodontal disease the administration of 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 to provide a process for the preparation of the above mentioned composition useful for the treatment periodontal disease. Yet objective of the present invention is to provide a process for the preparation of the above mentioned composition useful fot the treatment periodontal disease. Fluoroquinolones, as the active agent (drug) for the treatment of has been used for the treatment of periodontal diseases, are sparingly soluble in water. Many methods such as solid dispersion, recrystallization in organic solvents, use of co solvents and inclusion complexation in P-cyclodextrin have been employed to improve the solubility of such sparingly soluble drugs. Inclusion complex of drugs with P-cyclodextrin can be prepared by different methods such as kneading method, neutralization, spray drying etc. Kneading is the economic and easy method for preparing inclusion complexes. The present invention relates to in-situ forming of biodegradable compositions that can be used to aid in the restoration of the periodontium by the delivery of active agent( drug) to restore the periodontium. Accordingly, the present invention provides a composition, in the form of a gel, which is useful for the treatment of periodontal disease, which (a) a water-insoluble biodegradable polymer (b) a biocompatible, organic solvent (c) an active agent ( drug) and (d) a co-solvent capable of solubilizing the drug The cosolvent also acts as plasticizer and regulates the drug release rate from the polymer matrix. In a preferred embodiment of the invention the composition of the present invention comprises an inclusion complex of sparfloxacin with P-cyclodextrin. The composition of the present invention can be easily administered using a syringe and needle. The biodegradable polymer used in the composition of the present invention is a biodegradable polymer which dissolves in the biocompatible solvent. The preferred polymers used are those which have lower degree of crystallization and are more hydrophobic. Preferred polymers with the desired solubility parameters are the polylactides, polycaprolactones, and copolymers of these with each other and glycolide in which there are more amorphous regions to enhance solubility. Examples of the biodegradable polymers which can be used in the composition of the present invention may be selected from the group consisting of DL- Poly (lactide-co glycolide) It is also preferred that the solvent for the biodegradable polymer be non-toxic, water miscible, and otherwise biocompatible. Solvents that are toxic should not be used The solvents must also be biocompatible so that they do not cause severe tissue irritation or necrosis at the site of implantation. Furthermore, the solvent should be water miscible/ dispersible so that it will diffuse quickly into the body fluids and allow water to permeate into the polymer solution and cause it to coagulate or solidify. Examples of such solvents include Triacetin, N-methyl-2-pyrrolidone, Dimethyl sulfoxide, and ethyl lactate. The preferred solvents are triacetin, N-methyl-2-pyrrolidone and dimethyl sulfoxide because of their solvating ability and their compatibility. The solubility of the biodegradable polymers in the various solvents will differ depending upon their crystallinity, their hydrophilicity, hydrogen-bonding, and molecular weight. In the envisioned use of the system, the polymer solution is placed in a syringe and injected through a needle into the periodontal site. Once in place, the solvent dissipates, the remaining polymer solidifies, and a solid structure such as a membrane or implant is formed. The polymer will adhere to the surrounding tissue or bone by mechanical forces and can assume the shape of the periodontal pocket or surgical site. The term 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. The preferred drug which can be used with the formulation of the present invention may be selected from solid microporous implant systems, preferably sparfloxacin. To those skilled in the art, other drugs or biologically active agents that can be released in an aqueous environment can also be utilized in the formulation of the present invention The amount of drug or biologically active agent incorporated into the formulation 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 t 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 formulation be used to create a biological effect, but it can also be used to create the microporous structure needed for connective tissue in growth 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 for tissue in growth. 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 matrix. If 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 desired pore size. If the drug is also soluble in the polymer solution, then the distribution or mixing of the drug within the formulation 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. The active agent (drug) which can be used in the composition of the present invention may be selected from sparfloxacin, ciprofloxacin, tinidazole, doxycycline, gatifloxacin, ofloxacin, levofloxacin. According to the another feature of the present invention there is provided a process for the preparation of the above mentioned composition which comprises mixing (a) a water-insoluble biodegradable polymer (b) a biocompatible, organic solvent (c) an active agent ( drug) and (d) a co-solvent capable of solubilizing the drug The composition of the present invention can also be used to adhere gingival tissue to other tissue or other implants to tissue by virtue of its mechanical bonding. The solvent will dissipate and the polymer will solidify and entrap or encase the within the solid matrix. The release of drug from these solid implants will follow the same general rules for release of a drug from a monolithic polymeric device. The release of 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 composition of the present invention can be easily inserted at the site (periodontal pocket) using disposable syringes with No. 22 gauge needle. When the polymer solution containing drug comes in contact with the aqueous gingival crevicular fluid (GCF), the solvent diffuses out into the adjacent aqueous fluid and polymer will be precipitated out forming a solid matrix that would release the drug for a prolonged time. The polymer selected should have a long history of use in controlled release pharmaceuticals as wellas othwer biomedical applications. Thus when the composition of the present invention is injected into a soft-tissue defect (the defective site in the soft tissues of the gums and gingival [ tissues surrounding our teeth] i.e .periodontal pocket), it will fill that defect and provide a scaffold for natural collagen tissue to grow. The drug contained in the composition will be released within its matrix at a controlled rate until the drug is depleted. The details of the Invention are described in the Examples given below which are provided only to illustrate the invention and therefore they should not be construed to limit the scope of the invention EXAMPLE 1 Inclusion complex of sparfloxacin (392.40 mg) with P-cyclodextrin (1.134 g) was taken kneaded in glass mortar for 2 hours and then dried for 48 hours. The formation of inclusion complex formation was confirmed using IR spectroscopy, in vitro anti-bacterial study and in vitro dissolution study There was a significant improvement in the solubility of sparfloxacin as evident by the improvement in the dissolution rate as shown in Figure 1 and also improvement in the minimum inhibitory concentration for three representative bacteria such as Staphylococcus aureus, Pseudomonas aeroginosa and Escherichia coli (Table 1). Figure 1. In vitro dissolution studies of plain sparfloxacin, physical mixture of sparfloxacin and P-cyclodextrin and sparfloxacin -P-cyclodextrin inclusion complex Dissolution studies were carried out for the plain sparfloxacn, physical mixture of sparfloxacin and P-cyclodextrin and sparfloxacin -p-cyclodextrin complex using USP XXIII Dissolution Apparatus 2 ( Basket method). Results indicate that the dissolution rate of sparfloxacin -P-cyclodextrin was faster than plain sparfloxacin and physical mixture. Physical mixture did not demonstrate superiority against plain sparfloxacin in dissolution rate. This indicates that the complexation of sparfloxacin with P-cyclodextrin has improved the dissolution rate, which could be attributed to the increased solubility of the inclusion complex. Microbiological studies were conducted using Agar dilution susceptibility test.to determine the effect of complexation of drug in the minimum inhibitory concentration for bacteria such as Staphylococcus aureu (ATCC 25923), Escherichia coli (ATCC 25922) and Pseudomonas aeroginosa (ATCC 27853). Physical mixture was not selected for antimicrobial studies as there was no improvement in the solubility of the plain drug. Minimum inhibitory concentrations for plain sparfloxacin were 0.36 µg/ml, 0.45 µg/ml 0.08 µg/ml for Staphylococcus aureus, Pseudomonas aeroginosa and Escherichia coli respectively. While the minimum inhibitory concentration obtained from sparfloxacin-P-cyclodextrin complex for all the tested organisms could be attributed to the improved solubility leading to better diffusion of the complex in the bacterial cell walls for eliciting the antibacterial effect. EXAMPLE 2 Sparfloxacin-β-cyclodextrin complex 97.4 mg (~ to 25 mg ciprofloxacin) Propylene glycol 0.25 g Poly (lactide)-co- (glycolide) (75:25) 0.50 g Triacetin 4.25 g DL-Poly (lactide-co-glycolide) (75:25) (0.5 g) is dissolved in 4.25 g of triacetin in a polymer concentration of 10% w/w. Sparfloxacin-β-cyclodextrin complex ( 97.4 mg) was dissolved in propylene glycol ( 0.25 g) equivalent of 5% of total formulation. In vitro drug release studies was conducted 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 Figure 2. Figure 2. In vitro release profile of sparfloxacin from DL- Poly (Lactide-co-glycolide) (75:25) in situ gel implants The in vitro release studies indicate that the drugs are release in a biphasic manner, characeterised by an initial burst effect followed by slow and controlled release for a period of 60 days. Initial burst release could be attributed to the fact that there would be a lag time for the conversion of polymer solution into the solid gel matrix. For the formation of solid matrix, triacetiii should diffuse into the aqueous surroundings. During this lag period for the transition of the polymer solution into solid matrix, drug diffusion into the aqueous buffer would be faster leading to the burst effect in the initial stages. The fundamental parameters for the formulation of solid matrix include the water influx rate and gelation rate. Water influx rate is critical because it determines the rate at which the drug dissolve and therefore how readily they are able to diffuse through the implant. Once the gel is converted into solid matrix comprising of PLGA, further drug release is governed by diffusion through the pores formed in the solid matrix and polymer erosion. Another factor is the establishment of a concentration gradient between the polymeric matrix exterior and the core due to which the drug is transformed into the drug depleting zone in the vicinity of the matrix. Pores are created upon erosion of PLGA polymer matrix enabling the release of drug from the solid matrix. Diffusion through a pre-existing pore network in the polymer matrix and subsequent enhanced diffusion via erosion -induced pore enlargement and evolution have been regarded as a predominant drug release mechanism. Water penetrates the bulk of the device, preferentially attacking the chemical bonds in the amorphous phase and converting long polymer chains into shorter water soluble fragments. Further the drug release was controlled by incorporation of propylene glycol as co-solvent to dissolve the active drug as, for the drug to be released, the drug has to partition from its hydrophilic environment to a less hydrophilic environment of the polymer matrix and diffuse through the matrix into the aqueous medium. In vivo studies were conducted in the patients visiting to Department of Periodontics, College of Dental Surgery, KMC, MAHE, Manipal. Kasturba Hospital Ethical Committee approved the protocol of the study. Gingival crevicular fluid and saliva concentration of the drug was found to be above the minimum inhibitory concentration for periodontopathic bacteria as shown in Figure 3. After treatment with in situ gel implants, the concentration in GCF achieved a peak of 7.56± 1.06µg/mg at 1st h. and diminished gradually and the concentration of sparfloxacin at the end of 1440 h. (60 days) was 2.95 ±1.12 µg/mg. Concentration of sparfloxacin in saliva was considerably less compared to concentrations in GCF. Results of clinical evaluation after treatment with in situ gel implants containing sparfloxacin "P-cyclodextrin complex are summarized in the table above. It can be observed that there was highly significant reduction reduction in plaque index, gingival index and probing depth and there was a significant improvement in the gain of attachment level after 60 days of treatment with in situ gel implants containing sparfloxacin -p-cyclodextrin complex. Advantages of the invention The composition is useful for the treatment periodontal disease (i) which is safe, quick & easy to prepare and efiiceint (ii) which retains the effective concentration of the active agent ( drug) in the periodontal pocket, the infected site for a long time, say for a period in the range of 60 to 90 days (iii) the administration of which is convenient and quantitative on the basis of the amount of active agent (drug) to be delivered at the site. We claim 1. A composition in the form of a gel which is useful for the treatment of periodontal disease, that comprises of: (a) a, 10% w/w water-insoluble biodegradable polymer (b) a biocompatible organic solvent quantity sufficient (c) a 0.5% w/w of an active agent (drug) (d) a 5% w/w co-solvent capable of solubilizing the active agent (drug) 2. A composition as claimed in claim 1 wherein the biodegradable polymer uses is selected from those which have lower degree of crystallization and more hydrophobic such as polylactides, polycaprolactones and copolymers of these with each other and glycolide in which there are more amorphous regions to enhance solubility preferably, DL-Poly(lactide-coglycolide). 3. A composition as claimed in claims 1 and 2 where in the solvent used is selected fi'om Macetin, N-methyl-2-pyrrolidone, dimethyl sulfoxide, and ethyl acetate, preferred solvents being triacetin, N-methyl-2-pyrrolidone, dimethyl sulfoxide. 4. A composition as claimed in claims 1 to 3 wherein the active agent (drug) is selected from sparfloxacin, ciprofloxacin, tinidazole, doxycycline, gatifloxacin, ofloxacin, levofloxacin. 5. A composition wherein the ratio of polymer with active agent (drug) ranges from 1:20 6. A process for the preparation gel which is useful for the treatment of periodontal disease which comprises of DL-Poly (lactide-co-glycolide) is dissolved in triacetin. Sparfloxacin-p-cyclodextrin complex was dissolved in prolylene glycol. And then homogenously mixed both the solutions. 7. A process as claimed in claim 6 wherein the biodegradable polymer uses is selected from those which have lower degree of crystallization and are more hydrophobic such as polylactides, polycaprolactones and copolymers of these with each other and glycolide in which there are more amorphous regions to enhance solubility preferably, DL-Poly (lactide-coglycolide). 8. A process as claimed in claims 6 and 7 where in the solvent used is selected from triacetin, N-methyl-2-pyrrolidone, dimethyl sulfoxide. 9. A process as claimed in claims 6 to 8 wherein the active agent (drug) is selected from sparfloxacin, ciprofloxacin, tinidazole, doxycycline, gatifloxacin, ofloxacin, levofloxacin. 10. A process as claimed in claims 6 to 9 wherein the ratio of the polymer with the active agent (drug) ranges from 1: 20. 11. A composition in the form of a gel which is useful for the treatment of periodontal disease substantially as herein described with reference to the examples. 12. A process for the preparation of a gel as defined in claim 1, which is useful for the treatment of periodontal disease substantially as herein described with reference to the examples.

Documents:

0003-che-2004 abstract duplicate.pdf

0003-che-2004 claims duplicate.pdf

0003-che-2004 description (complete) duplicate.pdf

0003-che-2004 drawings duplicate.pdf

003-che-2004-abstract.pdf

003-che-2004-claims.pdf

003-che-2004-correspondnece-others.pdf

003-che-2004-correspondnece-po.pdf

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

003-che-2004-drawings.pdf

003-che-2004-form 1.pdf

003-che-2004-form 19.pdf