FIELD OF THE INVENTION

The present specification relates to controlled release pharmaceutical composition for periodontal disease comprising doxycycline or pharmaceutically acceptable salts thereof and metformin or pharmaceutically acceptable salts thereof. Methods of preparing such compositions are also provided.

BACKGROUND OF THE INVENTION

Periodontal diseases are the inflammatory disease affecting the periodontium. Gingivitis and periodontitis are the two major forms of the disease. Inflammation of the periodontium may result from many causes (e.g. bacteria, trauma). However, most forms of gingivitis and periodontitis result from the accumulation of tooth adherent microorganisms. The inflammation in the periodontal tissue is initiated by microbial plaque and bacterial infection, which can initiate destruction of the gingival tissues and periodontal attachment apparatus. Gingivitis is inflammation of the gingiva that does not result in clinical attachment loss. Gingivitis is a reversible disease. Therapy is aimed primarily at reduction of etiologic factors to reduce or eliminate inflammation, thereby allowing gingival tissues to heal. Appropriate supportive periodontal maintenance that includes personal and professional care is important in preventing re initiation of inflammation.

Periodontitis is inflammation of the gingiva and the adjacent attachment apparatus and is characterized by the progressive destruction of cementum, periodontal ligament and alveolar bone and subsequently, loss of teeth. Periodontitis destroys the attachment apparatus of teeth resulting in periodontal pocket formation and alteration of normal osseous anatomy. In the periodontal pocket the bacteria form a highly structured and complex biofilm. As this continues , the biofilm reach far subgingivally and it becomes difficult for the patient to reach it during oral hygiene practices. Prominent risk factors for development of chronic periodontitis include the presence of specific subgingival bacteria, tobacco use, diabetes, age, and male gender.

Doxycycline is a broad-spectrum antibiotic synthetically derived from oxytetracycline. Doxycycline is bacteriostatic, inhibiting bacterial protein synthesis due to disruption of transfer RNA and messenger RNA at ribosomal sites. Atridox is a FDA approved 10% doxycycline in a gel system indicated for use in the treatment of chronic adult periodontitis for a gain in clinical attachment, reduction in probing depth, and reduction in bleeding on probing. The structural formula of doxycycline hyclate is:

Metformin (1, 1 -dimethylbiguanide) HC1 is a secondgeneration biguanide, used to manage type 2 diabetes mellitus. There is no approved product of metformin for the management or treatment of periodontal disease.

Management of chronic periodontitis mainly involves the removal of the causative factors and repair, regenerate and maintain periodontal tissues. Scaling and root planing (SRP) is mainly used to remove plaque and calculus. Antibacterial agents have been used along with mechanical debridement in the management of periodontal infection. The effectiveness of all the methods are limited due to the lack of accessibility in the periodontal pocket. Periodontal pocket provides an ideal environment for the growth of anaerobic pathogenic bacteria. For the effective treatment, the antibiotic must reach the depth of the pocket and produce gingival fluid concentrations higher than the minimum inhibitory concentrations (MIC) of the suspected pathogens. The primary objectives of antibiotic therapy for patients with chronic periodontitis are to halt disease progression and to resolve inflammation. However, regeneration of lost periodontal structures or alveolar bone loss requires further treatment and which can be achieved by adjunctive surgical regeneration technique devices and materials. Regenerative therapy and other treatment modalities can be affected by several risk factors (eg, diabetes and tobacco use) which can diminish periodontal treatment outcomes. Therefore, there remains an unmet medical need for the effective treatment of periodontal disease which can inhibits bacterial growth in the periodontal pockets, and gingival/ sub-gingival plaque formation and additionally produce significant improvement in clinical and radiographic parameters in intrabony defects in patients with chronic periodontitis.

There is no drug product/composition of doxycycline and metformin combination which is globally approved or available. Moreover there is no combination composition which can be suitably inserted or placed or administered into a periodontal pocket for treating a periodontal disease.

Accordingly, the present invention provides controlled release pharmaceutical composition comprising doxycycline and metformin or pharmaceutically acceptable salts thereof, which is stable, suitable to be administered into a periodontal pocket, remains longer period of time in the periodontal pocket and could provide effective treatment of periodontal disease, for e.g. increases gain in clinical attachment, reduces probing depth and intrabony defects in patients with chronic periodontis. SUMMARY OF THE INVENTION

The present specification relates to controlled release pharmaceutical composition for periodontal disease comprising doxycycline or pharmaceutically acceptable salts thereof and metformin or pharmaceutically acceptable salts thereof. Methods of preparing such compositions are also provided.

In one aspect, the present specification relates to a controlled release pharmaceutical composition comprising: a) doxycycline or pharmaceutically acceptable salts thereof, b) metformin or pharmaceutically acceptable salts thereof, and wherein doxycycline and metformin or pharmaceutically acceptable salts thereof are present in a ratio of about 10:0.1 to 10:2.

In another aspect, the present specification relates to a controlled release pharmaceutical composition comprising: a) doxycycline or pharmaceutically acceptable salts thereof, b) metformin or pharmaceutically acceptable salts thereof, and wherein doxycycline and metformin or pharmaceutically acceptable salts thereof are present in a ratio of about 10: 1.

In another aspect, the present specification relates to a controlled release pharmaceutical composition comprising: a) doxycycline or pharmaceutically acceptable salts thereof, b) metformin or pharmaceutically acceptable salts thereof, and c) a pharmaceutically acceptable carrier system.

In yet another aspect, the present specification relates to a controlled release pharmaceutical composition comprising: a) doxycycline or pharmaceutically acceptable salts thereof, b) metformin or pharmaceutically acceptable salts thereof, and c) a pharmaceutically acceptable carrier system, wherein the said composition is suitable to be inserted or placed or administered into a periodontal pocket.

In another aspect, the present specification relates to a controlled release pharmaceutical composition comprising: a) doxycycline or pharmaceutically acceptable salts thereof, b) metformin or pharmaceutically acceptable salts thereof, and c) a pharmaceutically acceptable carrier system, wherein metformin or pharmaceutically acceptable salts thereof is having particle size of not more than 150 pm.

In another aspect, the present specification relates to a controlled release pharmaceutical composition comprising: a) doxycycline or pharmaceutically acceptable salts thereof, b) metformin or pharmaceutically acceptable salts thereof, and c) a pharmaceutically acceptable carrier system, wherein metformin or pharmaceutically acceptable salts thereof is present in the said composition in suspended form.

In yet another aspect, the present specification relates to a controlled release pharmaceutical composition comprising: a) doxycycline or pharmaceutically acceptable salts thereof, b) metformin or pharmaceutically acceptable salts thereof, and c) a pharmaceutically acceptable carrier system, wherein the said carrier system comprises one or more biodegradable polymers and one or more solvents. In yet another aspect, the present specification relates to a kit for periodontal administration comprising: a) drug component is suitably packed in one or more capsule or syringe or vial and the said drug component comprises doxycycline or pharmaceutically acceptable salts thereof and metformin or pharmaceutically acceptable salts thereof, and b) a pharmaceutically acceptable carrier component is suitably packed in one or more vial or syringe, wherein immediately prior to administration, the said drug component and the carrier component is admixed together to constitute a pharmaceutical composition and the said constituted composition is ready to be inserted or placed or administered into a periodontal pocket for treating a periodontal disease.

In yet another aspect, the present specification relates to use of controlled release pharmaceutical composition comprising doxycycline and metformin or pharmaceutically acceptable salts thereof for effective treatment of periodontal disease, for e.g. increases gain in clinical attachment, reduces probing depth and intrabony defects in patients with chronic periodontis.

In yet another aspect, the present specification relates to a method of treating chronic adult periodontitis for gain in clinical attachment, reduction in probing depth and intrabony defects, wherein the said method comprising administering to the said individual pharmaceutical composition comprising doxycycline or pharmaceutically acceptable salts and metformin or pharmaceutically acceptable salts.

BRIEF DESCRIPTION OF FIGURES

Figure 1: In-vitro dissolution study - release profile of doxycycline. Figure 2: In-vitro dissolution study - release profile of metformin.

DESCRIPTION OF THE INVENTION

The present specification relates to controlled release pharmaceutical composition for periodontal disease comprising doxycycline or pharmaceutically acceptable salts thereof and metformin or pharmaceutically acceptable salts thereof. Methods of preparing such compositions are also provided.

In one aspect, the present specification relates to a controlled release pharmaceutical composition comprising: a) doxycycline or pharmaceutically acceptable salts thereof, b) metformin or pharmaceutically acceptable salts thereof, and wherein doxycycline and metformin or pharmaceutically acceptable salts thereof are present in a ratio of about 10:0.1 to 10:2.

In another aspect, the present specification relates to a controlled release pharmaceutical composition comprising: a) doxycycline or pharmaceutically acceptable salts thereof, b) metformin or pharmaceutically acceptable salts thereof, and wherein doxycycline and metformin or pharmaceutically acceptable salts thereof are present in a ratio of about 10: 1.

In another aspect, the present specification relates to a controlled release pharmaceutical composition comprising: a) doxycycline or pharmaceutically acceptable salts thereof, b) metformin or pharmaceutically acceptable salts thereof, and c) a pharmaceutically acceptable carrier system. In yet another aspect, the present specification relates to a controlled release pharmaceutical composition comprising: a) doxycycline or pharmaceutically acceptable salts thereof, b) metformin or pharmaceutically acceptable salts thereof, and c) a pharmaceutically acceptable carrier system, wherein the said composition is suitable to be inserted or placed or administered into a periodontal pocket.

In another aspect, the present specification relates to a controlled release pharmaceutical composition comprising: a) doxycycline or pharmaceutically acceptable salts thereof, b) metformin or pharmaceutically acceptable salts thereof, and c) a pharmaceutically acceptable carrier system, wherein metformin or pharmaceutically acceptable salts thereof is having particle size of not more than 150 pm.

In another aspect, the present specification relates to a controlled release pharmaceutical composition comprising: a) doxycycline or pharmaceutically acceptable salts thereof, b) metformin or pharmaceutically acceptable salts thereof, and c) a pharmaceutically acceptable carrier system, wherein metformin or pharmaceutically acceptable salts thereof is present in the said composition in suspended form.

In yet another aspect, the present specification relates to a controlled release pharmaceutical composition comprising: a) doxycycline or pharmaceutically acceptable salts thereof, b) metformin or pharmaceutically acceptable salts thereof, and c) a pharmaceutically acceptable carrier system, wherein the said carrier system comprises one or more biodegradable polymers and one or more solvents.

In yet another aspect, the present specification relates to a kit for periodontal administration comprising: a) drug component is suitably packed in one or more capsule or syringe or vial and the said drug component comprises doxycycline or pharmaceutically acceptable salts thereof and metformin or pharmaceutically acceptable salts thereof, and b) a pharmaceutically acceptable carrier component is suitably packed in one or more vial or syringe, wherein immediately prior to administration, the said drug component and the carrier component is admixed together to constitute a pharmaceutical composition and the said constituted composition is ready to be inserted or placed or administered into a periodontal pocket for treating a periodontal disease.

In yet another aspect, the present specification relates to a method of treating chronic adult periodontitis for gain in clinical attachment, reduction in probing depth and intrabony defects, wherein the said method comprising administering to the said individual pharmaceutical composition comprising doxycycline or pharmaceutically acceptable salt and metformin or pharmaceutically acceptable salt.

As used herein, the term “controlled release" or “sustained release” or “prolong release” or “extended release” are used herein interchangeably and it refers to release of one or more active ingredients from the composition for a prolonged period of time at a controlled rate.

The term "pharmaceutical composition" is intended to encompass a combination including one or more active ingredients and pharmaceutically acceptable excipients or carriers. The excipients that are useful in preparing pharmaceutical compositions are generally safe, non- toxic, and are acceptable for pharmaceutical or cosmetic use. The composition of the present specifications may be in the form of lotions, liquids, solution, gel, spray etc. that are suitable for periodontal administration or suitable to be inserted or placed or administered into a periodontal pocket.

The periodontal pocket is defined as a pathologically deepened gingival sulcus around a tooth at the gingival margin. Gingival and periodontal pockets (also informally referred to as gum pockets) are dental terms indicating the presence of an abnormal depth of the gingival sulcus near the point at which the gingival tissue contacts the tooth.

The term “doxycycline” as used in the context of the present specification relates to the free base form, acid form, salt form, polymorphic crystalline or amorphous form, solvates, ethers, esters, etc. Preferably doxycycline is present in the pharmaceutically acceptable salt form, e.g. doxycycline hyclate. The amount of doxycycline or pharmaceutically acceptable salt thereof employed in the present composition is in the range of 35-60 mg, preferably in the range of 45-55 mg, e.g. 50 mg.

The term “metformin” as used in the context of the present specification relates to the free base form, acid form, salt form, polymorphic crystalline or amorphous form, solvates, ethers, esters, etc. Preferably metformin is present in the pharmaceutically acceptable salt form, e.g. metformin hydrochloride. The amount of metformin or pharmaceutically acceptable salt thereof employed in the present composition is in the range of 0.1-2 mg, e.g. 1 mg.

Pharmaceutically acceptable carrier system The pharmaceutically acceptable carrier system helps to prepare the composition suitable for periodontal administration. The carrier system comprises one or more biodegradable polymer and one or more solvent. The carrier system is provided in which one or more solid biodegradable polymer or copolymer is dissolved in one or more solvent, which is nontoxic and water miscible, to form a liquid solution. Once the polymer solution is placed into the body where there is sufficient water, the solvent dissipates or diffuses away from the polymer, leaving the polymer to coagulate or solidify into a solid structure which can serve as a barrier membrane. Alternatively, the liquid can be set outside of the body so that the dental professional can shape the material to fit the site of application.

Examples of biodegradable polymers which can be used in the present invention are but not limited to, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, and copolymers, terpolymers, or combinations or mixtures of the above materials.

Generally polymers which have lower degree of crystallization and are more hydrophobic are being preffered. These polymers and copolymers are more soluble in the biocompatible solvents than the highly crystalline polymers such as polyglycolide and chitin which also have a high degree of hydrogen-bonding. Preferred materials 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. Solvents according to the present invention, should be non-toxic, water miscible, and otherwise biocompatible. Solvents that are toxic should not be used to inject any material into a living body. 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 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 suitable solvents which can be used in the present specification are includes but not limited to, N-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, propylene glycol, acetone, methyl acetate, ethyl acetate, ethyl lactate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, dimethyl sulfone, tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid, N,N-diethyl-m- toluamide, and l-dodecylazacycloheptan-2-one. The preferred solvents are N-methyl- 2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, and acetone 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. Thus, not all of the biodegradable polymers will be soluble in the same solvent, but each polymer or copolymer should have its optimum solvent. Lower molecular-weight polymers will normally dissolve more readily in the solvents than high-molecular-weight polymers. As a result, the concentration of a polymer dissolved in the various solvents will differ depending upon type of polymer and its molecular weight. Conversely, the higher molecular-weight polymers will normally tend to coagulate or solidify faster than the very low-molecular-weight polymers. Moreover the higher molecular-weight polymers will tend to give higher solution viscosities than the low-molecular-weight materials. Thus for optimum injection efficiency, the molecular weight and the concentration of the polymer in the solvent have to be controlled. For polymers that tend to coagulate slowly, a solvent mixture can be used to increase the coagulation rate. Thus one liquid component of the mixture is a good solvent for the polymer, and the other component is a poorer solvent or a non-solvent. The two liquids are mixed at a ratio such that the polymer is still soluble but precipitates with the slightest physiological environment. By necessity, the solvent system must be miscible with both the polymer and water.

The carrier system may comprises some water-soluble materials. These water- soluble materials may be solid particles such as sugar or salt crystals, polymers not soluble in the biodegradable polymer or its carrier solvent, or polymers that are also soluble in the solvent for the biodegradable polymer.

Pharmaceutical Composition

The controlled release pharmaceutical compositions of the present specification primarily comprise two components or phase systems such as drug component and pharmaceutically acceptable carrier system component. The drugs or active ingredients are being dispersed in the pharmaceutically acceptable carrier system. The active ingredients may be dissolved or suspended in the carrier sytem. Such compositions are suitable to be inserted or placed or administered into a periodontal pocket for treating a periodontal disease and provides controlled release of the active ingredients for a prolog period of time, for example upto 7-15 days.

The drug component comprises doxycycline and metformin or pharmaceutically acceptable salts thereof as active ingredients. The doxycycline and metformin or pharmaceutically acceptable salts thereof are present in the drug component/compositions preferabely in a ratio of about 10:0.1 to 10:2, more preferabely 10:0.5 to 10:1.5, e.g. 10:1. The drugs component can be prepared by dispensing the active ingredients, shifting the acive ingredients through wire mesh sieves, and subsequently blending in a suitable blender. The drug comomponenent can be suitably packed in one or more capsule or syringe or vial. In order to get uniform blend and desired controlled release profile, the particle size of the both active ingredients are critical and suitably selected. The particle size (D90) of doxycycline or pharmaceutically acceptable salts thereof is preferably not more than 250 pm. On the other hand the particle size (D90) of metformin or pharmaceutically acceptable salts thereof is not more than 150 pm. The particle size of doxycycline or metformin or pharmaceutically acceptable salts thereof of the present specification is measured through particle size analyzer (Mastersizer) via dry or wet/liquid dispersion method.

The pharmaceutically acceptable carrier system comprises one or more biodegradable polymers and one or more solvents. The carrier system is prepared by mixing the one or more polymers with solvent through mechanical stirrer at slow speed (250-300 rpm) till the clear polymeric solution is obtained. Subsequently the polymer solution is filled and packed in vial or syringe. The biodegradable polymers in the carrier system aids to provide the desired controlled release profile. The carrier system provides the vehicle for the one or more active ingredients. The biodegradable polymers and solvents are suitably selected to prepare a carrier system which helps the active ingredients to be dispersed, dissolved or suspended form as required and provides reelase accordingly.

The controlled release pharmaceutical compositions of the present specification are prepared or constituted immediately prior to administration. The said drug component and the carrier component is admixed together to constitute a pharmaceutical composition and the said constituted composition is ready to be inserted or placed or administered into a periodontal pocket for treating a periodontal disease. The constituted composition can be administered via a applicator syringe with blunt canula suitable for periodontal administration. The viscosity of the constituted composition is preferably less than 9000 cps, more preferably less than 7000 cps. Depending upon the carrier system, the active ingredients may be dissolved or suspended in the constituted composition. Preferably metformin or pharmaceutically acceptable salts thereof is present in the constituted composition in suspended form and doxycycline or pharmaceutically acceptable salts thereof in dissolved form.

The controlled release pharmaceutical compositions of the present specification can be part of a kit or device and which comprises a drug component part suitably packed in capsule or syringe or vial and a pharmaceutically acceptable carrier component part suitably packed in a vial or syringe. In some cases the drug component syring and the carrier syringe coupled together and thereby allowing the contents of one syringe to be mixed with the contents of the other coupled syringe. A instruction guide/leaflet to constitute the composition may also present in the kit. The kit or device may further comprises a blunt cannula which could be used to administer the composition into a periodontal pocket for treating a periodontal disease.

The controlled release pharmaceutical composition of the present specification comprising doxycycline or pharmaceutically acceptable salt thereof and metformin or pharmaceutically acceptable salt thereof can be used in a patient in need thereof for the treatment of chronic adult periodontitis for a gain in clinical attachment, reduction in probing depth and intrabony defects, and reduction in bleeding on probing.

The controlled release pharmaceutical composition of the present specification comprising doxycycline or pharmaceutically acceptable salts thereof and metformin or pharmaceutically acceptable salts thereof can be used to increase gain in clinical attachment, reduces probing depth and intrabony defects in patients with chronic periodontis and can be used for effective treatment of periodontal disease.

The compositions of present specification is subjected to accelerated and long term stability studies. The specification will now be described in greater detail by reference to the following non-limiting examples.

EXAMPLES

Example 1: Controlled release pharmaceutical composition

Process:

Step A: Drug Component preparation:

1. Doxycycline and metformin are dispensed and sifted through wire mesh sieves.

2. The sifted materials were loaded in to double cone blender and mixed well.

3. The blended material was filled in a capsule of suitable size.

Step B: Carrier component preparation: 1. The polymers were mixed with the solvent through mechanical stirrer at slow speed (250-300 rpm) till the clear polymeric solution is obtained.

2. The polymeric solution was filled in a glass syringe.

Constituted Composition preparation:

1. Immediately prior to administration, the drug component of Step A is to be admixed with the carrier component of Step B.

2. The constituted composition is ready for administration into a periodontal pocket.

Example 2:

In-vitro dissolution study - release profile of doxycycline:

The release profile of doxycycline from the controlled release pharmaceutical compositions as per the present specification was evaluated through in vitro dissolution study by eppendorf method. The composition as per example lb and Atridox ^® (10% Doxycyline hyclate gel) were subjected to in vitro dissolution study by eppendorf method in pH 7.4 phosphate buffer. The volume of media was 1.5 mL. The dissolution was performed in water bath shaker at 20 rpm. Below is the representation of the resulted dissolution profile. Same is represented as Figure 1.

Example 3:

In-vitro dissolution study - release profile of metformin: The release profile of metformin HC1 from the compositions as per the present specification was evaluated through in vitro dissolution studies. Given the challenges of low volume of media in eppdorf method, the composition as per example lb was subjected to in vitro dissolution study using USP apparatus II in pH 7.4 phosphate buffer. The volume of media was 500 mL. Below is the representation of the resulted dissolution profile. Same is represented as Figure: 2.

Example 4:

Stability Study:

The stability of the composition comprising as per the present specification was evaluated through accelerated stability studies. The composition prepared according to example lb was subjected to stability study at various temperature and humidity conditions. The compositions was found to be stable at all conditions. Below table represents the study result data.

NMT- Not More Than

The results of above stability studies and release profiles indicates that the controlled rease pharmaceutical compositions comprising doxycycline and metformin or pharmaceuticaly acceptable salts thereof are stable and are suitable to be inserted or placed or administered into a periodontal pocket with controlled release of both doxycycline and metformin in a desirable manner to elicit desired treatment in targeted patients.