Title of Invention	BIOADHESIVE DRUG DELIVERY SYSTEM CONTAINING PARASYMPHATHOMIMETIC AGENT FOR THE TREATMENT OF XEROSTOMIA
Abstract	Xerqstomia is a disease caused by the dryness of mouth due to impaired salivary flow. The invention disclosed in these applications relates to a bioadhesive drug delivery system ! containing parasymphathomimetic agent for the treatment of xerostomia. This bioadhesive drug delivery system useful for the treatment of xerostomia comprises a matrix of hydrophilic polymers containing an parasymphathomimetic agent or its pharmaceutically acceptable salts and comp'ressible pharmaceutically acceptable exepients or their mixtures In addition, the present invention also provides a process for the preparation of the bioadhesive device for the treatment of xerostomia, employing method of granulation and compression. ~

Title of Invention

BIOADHESIVE DRUG DELIVERY SYSTEM CONTAINING PARASYMPHATHOMIMETIC AGENT FOR THE TREATMENT OF XEROSTOMIA

Abstract

Xerqstomia is a disease caused by the dryness of mouth due to impaired salivary flow. The invention disclosed in these applications relates to a bioadhesive drug delivery system ! containing parasymphathomimetic agent for the treatment of xerostomia. This bioadhesive drug delivery system useful for the treatment of xerostomia comprises a matrix of hydrophilic polymers containing an parasymphathomimetic agent or its pharmaceutically acceptable salts and comp'ressible pharmaceutically acceptable exepients or their mixtures In addition, the present invention also provides a process for the preparation of the bioadhesive device for the treatment of xerostomia, employing method of granulation and compression. ~

Full Text	BACKGROUND OF THE INVENTION This invention relates to bioadhesive drug delivery system containing parasymphathomimetic agent for the treatment of xerostomia. Xerostomia is a disease caused by the dryness of mouth due to impaired salivary flow. Xerostomia is the subjective sensation of oral dryness. One of the common etiologies for the xerostomia is dysfunction of salivary gland after radiation therapy for the head and neck cancer patients. Radiation therapy of patients with head and neck tumors usually causes damage to salivary gland. The parotid gland, which mainly consists of serous cells, is more sensitive to radiation damage among the salivary glands. A radiation dose as little as 20 Gy can cause permanent cessation of salivary flow if given as a single dose and with the conventional treatments for oral carcinoma (60-70 Gy), a rapid decrease in salivary flow occurs during the second week of radiotherapy. In addition to oral dryness and discomfort, patients with post-radiation xerostomia often have difficulties with mastication, swallowing, speech, and sleep. In addition they become susceptible to chronic oral overgrowth by Candida species and to a severe and rapidly progressive form of dental caries. Xerostomia alters mouth's buffering capacity and mechanical cleansing ability, thereby contributing to dental caries and progressive periodontal disease. The current therapy for xerostomia includes saliva substitutes and sialogogues to improve oral function and comfort. Saliva substitutes, mouth rinses and gustatory stimulants relieve the discomfort of xerostomia by temporarily wetting the oral mucosa and replacing some missing constitutes of saliva but are often abandoned for repeated water consumption as it will be the inconvenience to the patient to carry a water bottle along with him and this may lead to urinary frequency and nocturia. Treatment options including salivary stimulants and saliva substitutes are largely palliative and generally offer only short-term relief of symptoms. Some patients find these products useful but clinical experience suggests that they are not always well accepted. Sialogogues pharmacologically stimulate saliva production from intact responsive salivary glands. Parasymphathomimetic agents are the only drugs approved by the U. S. Food and Drug Administration as a sialogogue for the use of xerostomial symptoms. These cholinergic agonist who stimulates salivary secretion both in individuals with normal salivary gland function and in those with impaired salivary flow (xerostomia or dryness). These para symphathomimetic agent that functions primarily as a muscarinic agonist with mild beta adrenergic activity has been widely used in the treatment of xerostomia in head and neck cancer patients who were undergone the radiation therapy for the underlying tumour. This agent is subjected to an extensive and highly variable hepatic first - pass metabolism following oral administration with a reported bioavailability of 40-60 %. Because of its relatively short plasma half-life patients are routinely asked to take this agent (5.0/10.0 mg oral tablets) in divided daily doses every 4-6 hours with total dose of 20- 40 mg/day. Such frequent drug administration may reduce patient compUance and thus therapeutic efficacy. Apart from all these the drug is having untoward side effects like nausea, diarrhea, increased g.i. distress, when given orally. In addition to above the drug is rapidly inactivated by the esterases present in the gut and blood. More than half of the oral dose of this agent was excreted as unchanged drug or metabolite. These factors indicate a need of a controlled release bioadhesive drug dehvery systems for currently available Parasymphathomimetic agents. Discovering a new medicine is a very expensive and time-consuming undertaking. However, re-designing the modules and means to transport medicine into the body is a less demanding and more lucrative task. The developmental cost of a new drug may be about $250 million and takes about 12 years to reach the market place; whereas an existing drug molecule can get a second life with newer drug delivery systems that can be developed in half of the time with 20% cost of the new drug discovery. In addition to the cost containment, controlled and bioadhesive drug delivery systems can impart important advantages such as extending the duration of drug activity, which allows greater patient compUance owing to the elimination of multiple dosing schedules and reducing side effects due to optimization of blood concentration-time profiles. Hence, development of controlled and bioadhesive drug delivery system for presently available parasymphathomimetic agents would be an appropriate approach to overcome the complications like severe xerostomia, GI side effects, patient non-compliance associated with conventional therapy. Therefore, it is the main objective of the present invention to provide a bioadhesive drug delivery device for the treatment of xerostomia, which overcomes the severe dryness of mouth after radiation therapy, GI side effects and patient non-compliance of conventional treatment. It is another objective of the present invention to provide a device useful for the treatment of xerostomia, which employs matrix bioadhesive system as the carrier to transport the active agent (drug). Still another objective of the present invention to provide a bioadhesive drug delivery device useful for the treatment of xerostomia, which employs parasymphathomimetic agent as the active agent (drug). Yet another objective of the present invention to provide a bioadhesive drug delivery device useful for the treatment of xerostomia, which is convenient and quantitative on the basis of the amount of active substance (drug) to be delivered into systemic circulation through peroral absorption. Further objective of the present invention to provide a process for the preparation of the bioadhesive matrix device for the treatment of xerostomia, employing method of granulation and compression. From a technological point of view, an ideal oral mucoadhesive dosage form must have three properties: (a) It must maintain its position in the mouth for a few hours, (b) Release the drug in a controlled fashion and (c) Provide drug release in a unidirectional way towards the mucous A bioadhesive drug delivery system, therefore, be defined as a device, which has an ability to interact with biological materials, and is capable of being retained on the biological substrate for a period of time. One distinctive feature bioadhesion is that adhesion almost always occurs in the presence of water. These bioadhesive polymers swells and hydrates once it comes in contact with the fluid and forms a semipermanent adhesive bond with the mucous for sufficiently long time. This bond is responsible for the adhesion of these polymers with mucous membranes. Once the device is adhered onto the gingival area, it slowly releases the agent, which permeates into the skin and finally reaches the systemic circulation. Accordingly the present invention provides a Bioadhesive matrix drug delivery system useful for the treatment of xerostomia which comprises a matrix of hydrophilic polymers containing an parasymphathomimetic agent or its pharmaceutically acceptable salts and compressible pharmaceutically acceptable excipients or their mixtures According to another embodiment of the present invention there is provided a process for the preparation of the Bioadhesive matrix drug dehvery system useful for the treatment of xerostomia as defined above which comprises mixing a parasymphathomimetic agent with a matrix of hydrophilic polymer(s) along with other pharmaceutically acceptable excipients by conventional compressing methods. The matrix may be punched (compressed) with the help of single station punching machine, preferably 9.5 mm diameter flat punches. The bioadhesive polymers, which may be used as matrix may be selected from Sodium Carboxymethyl Cellulose, Carbopol 934P, Polycarbophil (PAA), Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose The term drug (agent) as used herein includes without limitation physiologically or pharmacologically active substances that are given for the treatment of xerostomia. Drugs used with this bioadhesive device. The drug used may preferably be pilocarpine nitrate. To those skilled in the art, other agents that can be permeated through oral mucosa and can be utilized in the described delivery system. The amount of drug, which is incorporated into the buccal device, depends upon the desired release profile, the concentration of the drug required for a biological effect and the length of time that the drug has to be released for the treatment. The lower limit of the drug incorporated into the delivery system is dependent simply upon the activity of the drug and the length of time needed for the treatment. In a preferred embodiment of the present invention, the bioadhesive matrix device may contain 5 mg of the drug, preferably, pilocarpine nitrate to obtain the desired release characteristics like maintenance of required therapeutic concentration of parasymphathomimetic agent for xerostomia. The bioadhesive matrix drug delivery system slowly releases the drug on to oral mucosa and then the drug is permeated through mucous membrane. The details of the invention are described in the Example 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 The bioadhesive matrix device of parasymphathomimetic agent was prepared by direct compression method. Carbopol 934P 6.0 mg Guargum 18.0 mg Directly compressible lactose 48.0 mg Microcrystalline cellulose 26.0 mg Talc 1.0 mg Magnesiun stearate 1.0 mg All the ingredients were first passed through sieve # 80. Then the required quantity of fillers were weighed accurately and mixed properly in a mortar with the help of a pestle to get a uniform blend. This was kept aside. Then the required polymer are weighed accurately and mixed in a mortar. After the two blends were mixed in geometric proportion to get the uniform distribution. Pilocarpine was weighed and mixed with the above blend in geometric proportion to get the uniform distribution of the drug. Finally other excipients like magnesium stearate and talc were mixed with the above blend. The matrix was punched with the help of single station punching machine with 9.5 mm diameter flat punches. Hardness was adjusted to 2.5-3.0 kg/cm and the thickness was adjusted to 1.05- 1.12 mm. Placebo bioadhesive matrix device was also prepared without adding the parasymphathomimetic agent in the similar way as described above. Table 1 gives the details about the matrix prepared. Bio-adhesive strength of the matrix was measured on a modified physical balance. The mucous membrane excised from the porcine cheek pouch was selected for the bioadhesive testing. The porcine cheek pouch was preserved in the buffer of pH 6.2 after trimming evenly from the sides. Cyanoacrylate adhesive was used to fix the matrix and the porcine cheek pouch to the two different supports of the instrument respectively. 20 )il of the buffer pH 6.2 was dropped on the matrix surface, and the matrix and the mucosa were brought in contact with a force of 10 G for about 3 min. Then the weight in gram, required to detach the tablets from the mucosal surface gave the measure of bioadhesive strength. Bioadhesive strength was found to be 11.38 ± 1.249 g. (n=5). When designing a oral bioadhesive drug release device, it is important to guarantee its adhesivity to the oral mucosa for a few hours. However, hydrophilic polymers, such as Carbopol 934P can be used to retain its bioadhesivity for 12 hours. An in vitro release study of the prepared matrix is shown in fig 1 of the drawing accompanying this specification. We opted pH 6.2 buffer to mimic the pH conditions in the mouth. Cumulative % drug release from the formulation in 12 hours was found to be 93.920 ± 1.028 (S.D.). The results of in vitro release studies were treated according to the first order rate equation, Higuchi's equation and Korsmeyer's equation to determine the rate and mechanism of drug release. It is evident from the information given in the fig 1 that the matrix prepared according to the Example 1 released the drug by first order kinetics till 4 hours with rate constant 4.83 x 10-3/min. The data treatment according to the Higuchi's equation and Korsmeyer's equation revealed that drug was released from the matrix predominantly by Fickian diffusion. Even though the matrix contained Carbopol 934P that swells inherently in aqueous solution, the presence of large quantity of Guargum would have prevented the swelling and hence change in the geometry of the tablets till 4 hours. After 4 hours enough swelling was found and non-Fickian release behavior was obtained, suggest that the release of Pilocarpine nitrate is controlled by the synergistic combination of diffusion as well as swelling of the bioadhesive material present in the matrix. In vivo studies To maintain the unidirectional flow of the drug through the mucoadhesed side, one side of the bioadhesive matrix device containing parasymphathomimetic agents was shielded with the help of BOPP film, which is a biaxially oriented polypropylene film with one side grafted with an adhesive. Healthy volunteers study Four healthy volunteers, three males and one female took part in this study. This study was done for optimization of the adhesion strength, adhesion time as far as formulation is concerned. Comfort, sense, non-irritation in the mouth was critically evaluated during this study. The average age of healthy volunteers used in the study were 23 ± 4 years and their weight was 62 ± 12 kg. Each healthy volunteer received a written form with instruction on how to use the tablets and a questionnaire to report any adverse effect (smarting sensations, dry mouth or irritability etc). Placebo matrix was also tried for the above study. In vivo absorption studies The matrixes with the backing membrane were applied to the gingival area of the healthy volunteers. After the specified time the matrix were removed fi-om the gingival area and dispersed in the 175 ml of pH 6.2 buffer with the help of magnetic stirrer for about 1 hour. In the mean time the oral cavity of the volunteer was rinsed thoroughly with the help of 20 ml of the 6.2 pH buffer and the washings were added to the beaker and volume was made up to 200 ml and centrifuged. The supernatant was analyzed for the drug content. By shielding the matrix fi:om one side in in vivo healthy volunteers study, we can just protect the drug from the environment of the oral cavity. The drug loss from the formulation can be overcome (swallowing). Taste problems as well as mucoadhesion problems through the other side to the cheek area were avoided. The matrix showed very good adhesion for a period of 12 hours. No volunteers felt any uncomfortable or smarting sensation during the considered period of 12 hours. /// vivo absorption of drug from the matrix is shown in fig 2. The study revealed that about 5.0 % of the drug remained unabsorbed from the dosage form when the matrix was analyzed for residual drug content after 12 hours. The result obtained in these studies indicate the gingival route to be a viable means of delivering parasymphathomimetic agent for xerostomia, allowing reduction in both the dose and dosing frequency over oral administration as well as avoiding possible poor absorption. EXAMPLE 2 The bioadhesive matrix device of parasymphathomimetic agent was prepared by direct compression method. Hydroxypropyl methyl cellulose K4M 28.0 mg Carbopol 934P 14.0 mg Direcdy compressible lactose 30.0 mg Microcrystalline cellulose 26.0 mg Talc 1.0 mg Magnesiun stearate 1.0 mg All the ingredients were first passed through sieve # 80. Then the required quantity of fillers were weighed accurately and mixed properly in a mortar with the help of a pestle to get a uniform blend. This was kept aside. Then the required polymer are weighed accurately and mixed in a mortar. After the two blends were mixed in geometric proportion to get the uniform distribution. Pilocarpine was weighed and mixed with the above blend in geometric proportion to get the uniform distribution of the drug. Finally other excipients like magnesium stearate and talc were mixed with the above blend. The matrix was punched with the help of single station punching machine with 9.5 mm diameter flat punches. EXAMPLE 3 Hydroxy propyl cellulose 10.0 mg Guargum 20.0 mg Directly compressible lactose 42.0 mg Microcrystalline cellulose 26.0 mg Talc 1.0 mg Magnesiun stearate 1.0 mg The bioadhesive matrix device of parasymphathomimetic agent was prepared using the above ingredients by directly compressible methods. All the ingredients were first passed through sieve # 80. Then the required quantity of fillers were weighed accurately and mixed properly in a mortar with the help of a pestle to get a uniform blend. This was kept aside. Then the required polymer are weighed accurately and mixed in a mortar. After the two blends were mixed in geometric proportion to get the uniform distribution. Pilocarpine was weighed and mixed with the above blend in geometric proportion to get the uniform distribution of the drug. Finally other excipients like magnesium stearate and talc were mixed with the above blend. The matrix was punched with the help of single station punching machine with 9.5 mm diameter flat punches. EXAMPLE 4 This example deals with the effect of prepared bioadhesive matrix drug delivery system containing parasymphathomimetic agents useful for the treatment of xerostomia on the post irridated patients having head and neck cancer. We included 21 patients in our clinical trial. Subjective evaluation of the patients was done at the beginning (Base line response), at 30 days interval, at the end of the study. We carried out the study for a period of two and half months. Eligible patients had generally received greater than 50 Gy (55-60 rad of external radiation at the rate of 200 cGy per day, 5 days per week) of the external beam radiation therapy for head and neck cancer more than 4 months before entering into the study. The average age was 55 ±13 years. 17 patients were male and 4 patients were female. All had clinically significant xerostomia. All patients had at least one parotid gland and some indication of residual salivary function as shown by visual evidence of moisture in the oral cavity. In this study 11 patients were assigned with bioadhesive matrix device (prepared by the process described in Example 1) and 10 were assigned with placebo bioadhesive matrix as prepared by the process described in the example 1 without containing the drug. At each scheduled visit, a subjective assessment of efficacy was performed using visual analogue scale (VAS). The scale was set up with negative responses "very dry", "extremely uncomfortable", or "very difficult" as the left anchor and positive responses "not dry", "comfortable", or "easy", as the right anchor. Patients answered quesfions concerning dryness of the mouth, oral comfort, ability to speak, chew, swallow, sleep and wear dentures. They were also asked a global question relating to the overall condition of xerostomia. Addition to this they were also asked general question about the medication, route of administration, comfortability with the dosage form, and about quality of life. Clinical outcome Improvement in overall condition of the xerostomia. This was assessed, based on his/her recollection of the severity of the symptoms, before initiating treatment. The global assessment was measured by noting the patients own sense of improvement based on recall of the baseline severity. Effect of Pilocarpine on symptoms of postradiation xerostomia Out of 11 Pilocarpine treated patients one patient never came for follow up. One patient discontinued the medication after one month, as he was feeling inconvenient to put the medication at the gingival area. Out of 10 placebos treated patients all came for follow up regularly on stated day. Initially there was not significant difference between two groups as far as pharmacological effect is concerned, but during their first follow up (after one month), and second follow up (after two month), drastic improvement in the condition is noted when compared with the placebo treated group. The table 2 and 3 shows that patients accepted the formulations and their quality of life has increased. They are not feeling any discomfort and they can lead their normal life. This also gives the information that the bioadhesive matrix device is better than the Placebo i.e. the drug is showing its pharmacological activity in the said formulation. This also shows that there are no side effects and patients can carry out their routine day-to-day activity with this formulation placed on their gingival. Overall there is an improvement in the patient conditions after application of this drug delivery system. Advantages of the invention 1. The device is useful for the treatment of xerostomia, for preventing Gl side effects 2. The device improves patient compliance. 3. The device employ bioadhesive matrix as the carrier to transport the active agent (drug), which helps in the permeation of drug through oral mucosa in a controlled manner. 4. The device helps in retaining the effective concentration of the active substance (drug) in plasma for a long time say for a period in the range of 0 to 8 hours. Therefore sustained release of intented agent through oral mucosa can be achieved with thee device. 5. The device is convenient and quantitative on the basis of the amount of active substance (drug) to be delivered into systemic circulation through oral mucosa. 6. The device is user friendly and can be employed without the help of any skilled personal 7. The device help[s in maintaining constant blood levels, reduces side effects, avoids first-pass metabolism of drug, bypasses the drug from GI tract, and interruption or termination of treatment when necessary is possible and dose dumping never occurs. Thus the bioadhesive drug delivery system offers many advantages over the conventional dosage forms or controlled release peroral delivery systems. We Claim 1. A bioadhesive matrix drug delivery system useful for the treatment of xerostomia, which comprises a matrix of hydrophilic polymers containing parasymphathomimetic agent and comprisable pharmaceutically acceptable exepients or their mixtures . 2. A bioadhesive matrix drug delivery system as claimed in claim 1 wherein the concentration of the bioadhesive polymer(s) used ranges from 0.25-5%. 3. A bioadhesive matrix drug delivery system as claimed in claims 1 & 2 wherein the drug used is selected from the classes of parasymphathomimetic agents and their pharamceuticaly acceptable salts, preferably pilocarpine. 4. A bioadhesive matrix device as claimed in claims 1 to 3, wherein the ratio of the polymers used (hydrophilic polymer) ranges from 0.25:4.75 to 4.75:0.25. 5. A process for the preparation of bioadhesive matrix drug delivery system useful for the treatment of xerostomia as defined in claim 1,which comprises which comprises mixing a parasymphathomimetic agent or its pharamaceutically acceptable salts with a matrix of hydrophilic polymer(s) along with other compressible pharmaceutically acceptable excipients and compressing by conventional methods the resulting mixture to the desired size 6. A process as claimed in claim 5, wherein the ratio of the polymers used (hydrophilic polymer) ranges from 0.25:4.75 to 4.75:0.25. 7. A process as claimed in claims 5 & 6 wherein the drug (agent) used is selected from parasymphathomimetic agents, specifically pilocarpine. 8. A process as claimed in claims 5 to 7 wherein the concentration of the bioadhesive polymer(s) used ranges from 0.25-5%. 9. A process as claimed in claims 5 to 8 wherein the drug used is selected from the classes of parasymphathomimetic agents and their pharamceuticaly acceptable salts, preferably pilocarpine nitrate, pilocarpine hydrochloride, pilocarpine sulphate, pilocarpine mesylate, pilocarpine maleate, pilocarpine citrate. 10. A process for the preparation of bioadhesive matrix drug delivery system useful for the treatment of xerostomia substantially as herein described with reference to the Example 1. 11. A bioadhesive matrix drug delivery system useful for the treatment of xerostomia substantially as herein described with reference to the Example 1.

Full Text

BACKGROUND OF THE INVENTION
This invention relates to bioadhesive drug delivery system containing parasymphathomimetic agent for the treatment of xerostomia. Xerostomia is a disease caused by the dryness of mouth due to impaired salivary flow.
Xerostomia is the subjective sensation of oral dryness. One of the common etiologies for the xerostomia is dysfunction of salivary gland after radiation therapy for the head and neck cancer patients. Radiation therapy of patients with head and neck tumors usually causes damage to salivary gland. The parotid gland, which mainly consists of serous cells, is more sensitive to radiation damage among the salivary glands. A radiation dose as little as 20 Gy can cause permanent cessation of salivary flow if given as a single dose and with the conventional treatments for oral carcinoma (60-70 Gy), a rapid decrease in salivary flow occurs during the second week of radiotherapy. In addition to oral dryness and discomfort, patients with post-radiation xerostomia often have difficulties with mastication, swallowing, speech, and sleep. In addition they become susceptible to chronic oral overgrowth by Candida species and to a severe and rapidly progressive form of dental caries. Xerostomia alters mouth's buffering capacity and mechanical cleansing ability, thereby contributing to dental caries and progressive periodontal disease.
The current therapy for xerostomia includes saliva substitutes and sialogogues to improve oral function and comfort. Saliva substitutes, mouth rinses and gustatory stimulants relieve the discomfort of xerostomia by temporarily wetting the oral mucosa and replacing some missing constitutes of saliva but are often abandoned for repeated water consumption as it will be the inconvenience to the patient to carry a water bottle along with him and this may lead to urinary frequency and nocturia. Treatment options including salivary stimulants and saliva substitutes are largely palliative and generally offer only short-term relief of symptoms. Some patients find these products useful but clinical experience suggests that they are not always well accepted.
Sialogogues pharmacologically stimulate saliva production from intact responsive salivary glands. Parasymphathomimetic agents are the only drugs approved by the U. S. Food and Drug Administration as a sialogogue for the use of xerostomial symptoms. These cholinergic agonist who stimulates salivary secretion both in individuals with normal salivary gland function and in those with impaired salivary flow (xerostomia or dryness). These para

symphathomimetic agent that functions primarily as a muscarinic agonist with mild beta adrenergic activity has been widely used in the treatment of xerostomia in head and neck cancer patients who were undergone the radiation therapy for the underlying tumour. This agent is subjected to an extensive and highly variable hepatic first - pass metabolism following oral administration with a reported bioavailability of 40-60 %. Because of its relatively short plasma half-life patients are routinely asked to take this agent (5.0/10.0 mg oral tablets) in divided daily doses every 4-6 hours with total dose of 20- 40 mg/day. Such frequent drug administration may reduce patient compUance and thus therapeutic efficacy. Apart from all these the drug is having untoward side effects like nausea, diarrhea, increased g.i. distress, when given orally. In addition to above the drug is rapidly inactivated by the esterases present in the gut and blood. More than half of the oral dose of this agent was excreted as unchanged drug or metabolite.
These factors indicate a need of a controlled release bioadhesive drug dehvery systems for currently available Parasymphathomimetic agents. Discovering a new medicine is a very expensive and time-consuming undertaking. However, re-designing the modules and means to transport medicine into the body is a less demanding and more lucrative task. The developmental cost of a new drug may be about $250 million and takes about 12 years to reach the market place; whereas an existing drug molecule can get a second life with newer drug delivery systems that can be developed in half of the time with 20% cost of the new drug discovery. In addition to the cost containment, controlled and bioadhesive drug delivery systems can impart important advantages such as extending the duration of drug activity, which allows greater patient compUance owing to the elimination of multiple dosing schedules and reducing side effects due to optimization of blood concentration-time profiles.
Hence, development of controlled and bioadhesive drug delivery system for presently available parasymphathomimetic agents would be an appropriate approach to overcome the complications like severe xerostomia, GI side effects, patient non-compliance associated with conventional therapy.
Therefore, it is the main objective of the present invention to provide a bioadhesive drug delivery device for the treatment of xerostomia, which overcomes the severe dryness of mouth after radiation therapy, GI side effects and patient non-compliance of conventional treatment.

It is another objective of the present invention to provide a device useful for the treatment of xerostomia, which employs matrix bioadhesive system as the carrier to transport the active agent (drug).
Still another objective of the present invention to provide a bioadhesive drug delivery device useful for the treatment of xerostomia, which employs parasymphathomimetic agent as the active agent (drug).
Yet another objective of the present invention to provide a bioadhesive drug delivery device useful for the treatment of xerostomia, which is convenient and quantitative on the basis of the amount of active substance (drug) to be delivered into systemic circulation through peroral absorption.
Further objective of the present invention to provide a process for the preparation of the bioadhesive matrix device for the treatment of xerostomia, employing method of granulation and compression.
From a technological point of view, an ideal oral mucoadhesive dosage form must have three properties: (a) It must maintain its position in the mouth for a few hours, (b) Release the drug in a controlled fashion and (c) Provide drug release in a unidirectional way towards the mucous
A bioadhesive drug delivery system, therefore, be defined as a device, which has an ability to interact with biological materials, and is capable of being retained on the biological substrate for a period of time. One distinctive feature bioadhesion is that adhesion almost always occurs in the presence of water. These bioadhesive polymers swells and hydrates once it comes in contact with the fluid and forms a semipermanent adhesive bond with the mucous for sufficiently long time. This bond is responsible for the adhesion of these polymers with mucous membranes. Once the device is adhered onto the gingival area, it slowly releases the agent, which permeates into the skin and finally reaches the systemic circulation.
Accordingly the present invention provides a Bioadhesive matrix drug delivery system useful for the treatment of xerostomia which comprises a matrix of hydrophilic polymers containing an parasymphathomimetic agent or its pharmaceutically acceptable salts and compressible pharmaceutically acceptable excipients or their mixtures

According to another embodiment of the present invention there is provided a process for the preparation of the Bioadhesive matrix drug dehvery system useful for the treatment of xerostomia as defined above which comprises mixing a parasymphathomimetic agent with a matrix of hydrophilic polymer(s) along with other pharmaceutically acceptable excipients by conventional compressing methods.
The matrix may be punched (compressed) with the help of single station punching machine, preferably 9.5 mm diameter flat punches.
The bioadhesive polymers, which may be used as matrix may be selected from Sodium Carboxymethyl Cellulose, Carbopol 934P, Polycarbophil (PAA), Hydroxy Propyl Cellulose, Hydroxy Propyl Methyl Cellulose
The term drug (agent) as used herein includes without limitation physiologically or pharmacologically active substances that are given for the treatment of xerostomia. Drugs used with this bioadhesive device. The drug used may preferably be pilocarpine nitrate. To those skilled in the art, other agents that can be permeated through oral mucosa and can be utilized in the described delivery system. The amount of drug, which is incorporated into the buccal device, depends upon the desired release profile, the concentration of the drug required for a biological effect and the length of time that the drug has to be released for the treatment. The lower limit of the drug incorporated into the delivery system is dependent simply upon the activity of the drug and the length of time needed for the treatment.
In a preferred embodiment of the present invention, the bioadhesive matrix device may contain 5 mg of the drug, preferably, pilocarpine nitrate to obtain the desired release characteristics like maintenance of required therapeutic concentration of parasymphathomimetic agent for xerostomia.
The bioadhesive matrix drug delivery system slowly releases the drug on to oral mucosa and then the drug is permeated through mucous membrane.
The details of the invention are described in the Example 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
The bioadhesive matrix device of parasymphathomimetic agent was prepared by direct compression method.
Carbopol 934P 6.0 mg
Guargum 18.0 mg
Directly compressible lactose 48.0 mg
Microcrystalline cellulose 26.0 mg
Talc 1.0 mg
Magnesiun stearate 1.0 mg
All the ingredients were first passed through sieve # 80. Then the required quantity of fillers were weighed accurately and mixed properly in a mortar with the help of a pestle to get a uniform blend. This was kept aside. Then the required polymer are weighed accurately and mixed in a mortar. After the two blends were mixed in geometric proportion to get the uniform distribution. Pilocarpine was weighed and mixed with the above blend in geometric proportion to get the uniform distribution of the drug. Finally other excipients like magnesium stearate and talc were mixed with the above blend.
The matrix was punched with the help of single station punching machine with 9.5 mm diameter flat punches. Hardness was adjusted to 2.5-3.0 kg/cm and the thickness was adjusted to 1.05- 1.12 mm.
Placebo bioadhesive matrix device was also prepared without adding the parasymphathomimetic agent in the similar way as described above.
Table 1 gives the details about the matrix prepared.

Bio-adhesive strength of the matrix was measured on a modified physical balance. The mucous membrane excised from the porcine cheek pouch was selected for the bioadhesive testing. The porcine cheek pouch was preserved in the buffer of pH 6.2 after trimming evenly from the sides. Cyanoacrylate adhesive was used to fix the matrix and the porcine cheek pouch to the two different supports of the instrument respectively. 20 )il of the buffer pH 6.2 was dropped on the matrix surface, and the matrix and the mucosa were brought in contact with a force of 10 G for about 3 min. Then the weight in gram, required to detach the tablets from the mucosal surface gave the measure of bioadhesive strength.
Bioadhesive strength was found to be 11.38 ± 1.249 g. (n=5). When designing a oral bioadhesive drug release device, it is important to guarantee its adhesivity to the oral mucosa for a few hours. However, hydrophilic polymers, such as Carbopol 934P can be used to retain its bioadhesivity for 12 hours.
An in vitro release study of the prepared matrix is shown in fig 1 of the drawing accompanying this specification. We opted pH 6.2 buffer to mimic the pH conditions in the mouth. Cumulative % drug release from the formulation in 12 hours was found to be 93.920 ± 1.028 (S.D.). The results of in vitro release studies were treated according to the first order rate equation, Higuchi's equation and Korsmeyer's equation to determine the rate and mechanism of drug release.
It is evident from the information given in the fig 1 that the matrix prepared according to the Example 1 released the drug by first order kinetics till 4 hours with rate constant 4.83 x 10-3/min. The data treatment according to the Higuchi's equation and Korsmeyer's equation revealed that drug was released from the matrix predominantly by Fickian diffusion. Even though the matrix contained Carbopol 934P that swells inherently in aqueous solution, the presence of large quantity of Guargum would have prevented the swelling and hence change in the geometry of the tablets till 4 hours. After 4 hours enough swelling was found and non-Fickian release behavior was obtained, suggest that the release of Pilocarpine nitrate is controlled by the synergistic combination of diffusion as well as swelling of the bioadhesive material present in the matrix.

In vivo studies
To maintain the unidirectional flow of the drug through the mucoadhesed side, one side of the bioadhesive matrix device containing parasymphathomimetic agents was shielded with the help of BOPP film, which is a biaxially oriented polypropylene film with one side grafted with an adhesive.
Healthy volunteers study
Four healthy volunteers, three males and one female took part in this study. This study was done for optimization of the adhesion strength, adhesion time as far as formulation is concerned. Comfort, sense, non-irritation in the mouth was critically evaluated during this study. The average age of healthy volunteers used in the study were 23 ± 4 years and their weight was 62 ± 12 kg. Each healthy volunteer received a written form with instruction on how to use the tablets and a questionnaire to report any adverse effect (smarting sensations, dry mouth or irritability etc). Placebo matrix was also tried for the above study.
In vivo absorption studies
The matrixes with the backing membrane were applied to the gingival area of the healthy volunteers. After the specified time the matrix were removed fi-om the gingival area and dispersed in the 175 ml of pH 6.2 buffer with the help of magnetic stirrer for about 1 hour. In the mean time the oral cavity of the volunteer was rinsed thoroughly with the help of 20 ml of the 6.2 pH buffer and the washings were added to the beaker and volume was made up to 200 ml and centrifuged. The supernatant was analyzed for the drug content.
By shielding the matrix fi:om one side in in vivo healthy volunteers study, we can just protect the drug from the environment of the oral cavity. The drug loss from the formulation can be overcome (swallowing). Taste problems as well as mucoadhesion problems through the other side to the cheek area were avoided. The matrix showed very good adhesion for a period of 12 hours. No volunteers felt any uncomfortable or smarting sensation during the considered period of 12 hours.
/// vivo absorption of drug from the matrix is shown in fig 2. The study revealed that about 5.0 % of the drug remained unabsorbed from the dosage form when the matrix was analyzed for residual drug content after 12 hours. The result obtained in these studies indicate the gingival route to be a viable means of delivering parasymphathomimetic agent for xerostomia, allowing reduction

in both the dose and dosing frequency over oral administration as well as avoiding possible poor absorption.
EXAMPLE 2
The bioadhesive matrix device of parasymphathomimetic agent was prepared by direct compression method.
Hydroxypropyl methyl cellulose K4M 28.0 mg
Carbopol 934P 14.0 mg
Direcdy compressible lactose 30.0 mg
Microcrystalline cellulose 26.0 mg
Talc 1.0 mg
Magnesiun stearate 1.0 mg
All the ingredients were first passed through sieve # 80. Then the required quantity of fillers were weighed accurately and mixed properly in a mortar with the help of a pestle to get a uniform blend. This was kept aside. Then the required polymer are weighed accurately and mixed in a mortar. After the two blends were mixed in geometric proportion to get the uniform distribution. Pilocarpine was weighed and mixed with the above blend in geometric proportion to get the uniform distribution of the drug. Finally other excipients like magnesium stearate and talc were mixed with the above blend.
The matrix was punched with the help of single station punching machine with 9.5 mm diameter flat punches.
EXAMPLE 3
Hydroxy propyl cellulose 10.0 mg
Guargum 20.0 mg
Directly compressible lactose 42.0 mg
Microcrystalline cellulose 26.0 mg
Talc 1.0 mg
Magnesiun stearate 1.0 mg
The bioadhesive matrix device of parasymphathomimetic agent was prepared using the above ingredients by directly compressible methods.

All the ingredients were first passed through sieve # 80. Then the required quantity of fillers were weighed accurately and mixed properly in a mortar with the help of a pestle to get a uniform blend. This was kept aside. Then the required polymer are weighed accurately and mixed in a mortar. After the two blends were mixed in geometric proportion to get the uniform distribution. Pilocarpine was weighed and mixed with the above blend in geometric proportion to get the uniform distribution of the drug. Finally other excipients like magnesium stearate and talc were mixed with the above blend.
The matrix was punched with the help of single station punching machine with 9.5 mm diameter flat punches.
EXAMPLE 4
This example deals with the effect of prepared bioadhesive matrix drug delivery system containing parasymphathomimetic agents useful for the treatment of xerostomia on the post irridated patients having head and neck cancer.
We included 21 patients in our clinical trial. Subjective evaluation of the patients was done at the beginning (Base line response), at 30 days interval, at the end of the study. We carried out the study for a period of two and half months.
Eligible patients had generally received greater than 50 Gy (55-60 rad of external radiation at the rate of 200 cGy per day, 5 days per week) of the external beam radiation therapy for head and neck cancer more than 4 months before entering into the study. The average age was 55 ±13 years. 17 patients were male and 4 patients were female. All had clinically significant xerostomia. All patients had at least one parotid gland and some indication of residual salivary function as shown by visual evidence of moisture in the oral cavity. In this study 11 patients were assigned with bioadhesive matrix device (prepared by the process described in Example 1) and 10 were assigned with placebo bioadhesive matrix as prepared by the process described in the example 1 without containing the drug.
At each scheduled visit, a subjective assessment of efficacy was performed using visual analogue scale (VAS). The scale was set up with negative responses "very dry", "extremely uncomfortable", or "very difficult" as the left anchor and positive responses "not dry", "comfortable", or "easy", as the right anchor. Patients answered quesfions concerning dryness of the mouth, oral comfort, ability to speak, chew, swallow, sleep and wear dentures. They

were also asked a global question relating to the overall condition of xerostomia. Addition to this they were also asked general question about the medication, route of administration, comfortability with the dosage form, and about quality of life.
Clinical outcome
Improvement in overall condition of the xerostomia. This was assessed, based on his/her recollection of the severity of the symptoms, before initiating treatment. The global assessment was measured by noting the patients own sense of improvement based on recall of the baseline severity.
Effect of Pilocarpine on symptoms of postradiation xerostomia
Out of 11 Pilocarpine treated patients one patient never came for follow up. One patient discontinued the medication after one month, as he was feeling inconvenient to put the medication at the gingival area. Out of 10 placebos treated patients all came for follow up regularly on stated day.

Initially there was not significant difference between two groups as far as pharmacological effect is concerned, but during their first follow up (after one month), and second follow up (after two month), drastic improvement in the condition is noted when compared with the placebo treated group.

The table 2 and 3 shows that patients accepted the formulations and their quality of life has increased. They are not feeling any discomfort and they can lead their normal life. This also gives the information that the bioadhesive matrix device is better than the Placebo i.e. the drug is showing its pharmacological activity in the said formulation. This also shows that there are no side effects and patients can carry out their routine day-to-day activity with this formulation placed on their gingival. Overall there is an improvement in the patient conditions after application of this drug delivery system.
Advantages of the invention
1. The device is useful for the treatment of xerostomia, for preventing Gl side effects
2. The device improves patient compliance.
3. The device employ bioadhesive matrix as the carrier to transport the active agent (drug),
which helps in the permeation of drug through oral mucosa in a controlled manner.
4. The device helps in retaining the effective concentration of the active substance (drug) in
plasma for a long time say for a period in the range of 0 to 8 hours. Therefore sustained
release of intented agent through oral mucosa can be achieved with thee device.
5. The device is convenient and quantitative on the basis of the amount of active substance
(drug) to be delivered into systemic circulation through oral mucosa.

6. The device is user friendly and can be employed without the help of any skilled personal
7. The device help[s in maintaining constant blood levels, reduces side effects, avoids first-pass metabolism of drug, bypasses the drug from GI tract, and interruption or termination of treatment when necessary is possible and dose dumping never occurs.
Thus the bioadhesive drug delivery system offers many advantages over the conventional dosage forms or controlled release peroral delivery systems.

We Claim
1. A bioadhesive matrix drug delivery system useful for the treatment of xerostomia, which comprises a matrix of hydrophilic polymers containing parasymphathomimetic agent and comprisable pharmaceutically acceptable exepients or their mixtures .
2. A bioadhesive matrix drug delivery system as claimed in claim 1 wherein the concentration of the bioadhesive polymer(s) used ranges from 0.25-5%.
3. A bioadhesive matrix drug delivery system as claimed in claims 1 & 2 wherein the drug used is selected from the classes of parasymphathomimetic agents and their pharamceuticaly acceptable salts, preferably pilocarpine.
4. A bioadhesive matrix device as claimed in claims 1 to 3, wherein the ratio of the polymers used (hydrophilic polymer) ranges from 0.25:4.75 to 4.75:0.25.
5. A process for the preparation of bioadhesive matrix drug delivery system useful for the treatment of xerostomia as defined in claim 1,which comprises which comprises mixing a parasymphathomimetic agent or its pharamaceutically acceptable salts with a matrix of hydrophilic polymer(s) along with other compressible pharmaceutically acceptable excipients and compressing by conventional methods the resulting mixture to the desired size
6. A process as claimed in claim 5, wherein the ratio of the polymers used (hydrophilic polymer) ranges from 0.25:4.75 to 4.75:0.25.
7. A process as claimed in claims 5 & 6 wherein the drug (agent) used is selected from parasymphathomimetic agents, specifically pilocarpine.
8. A process as claimed in claims 5 to 7 wherein the concentration of the bioadhesive polymer(s) used ranges from 0.25-5%.
9. A process as claimed in claims 5 to 8 wherein the drug used is selected from the classes of parasymphathomimetic agents and their pharamceuticaly acceptable salts, preferably pilocarpine nitrate, pilocarpine hydrochloride, pilocarpine sulphate, pilocarpine mesylate, pilocarpine maleate, pilocarpine citrate.

10. A process for the preparation of bioadhesive matrix drug delivery system useful for the
treatment of xerostomia substantially as herein described with reference to the Example 1.
11. A bioadhesive matrix drug delivery system useful for the treatment of xerostomia
substantially as herein described with reference to the Example 1.

Documents:

354-che-2004 abstract duplicate.pdf

354-che-2004 claims duplicate.pdf

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

354-che-2004 drawings duplicate.pdf

354-che-2004-claims.pdf

354-che-2004-correspondnece-others.pdf

354-che-2004-correspondnece-po.pdf

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

354-che-2004-drawings.pdf

354-che-2004-form 1.pdf

354-che-2004-form 19.pdf

« Previous Patent

Next Patent »

Patent Number

222658

Indian Patent Application Number

354/CHE/2004

PG Journal Number

47/2008

Publication Date

21-Nov-2008

Grant Date

20-Aug-2008

Date of Filing

19-Apr-2004

Name of Patentee

THE MANIPAL COLLEGE OF PHARMACEUTICAL SCIENCES

Applicant Address

MADHAV NAGAR, MANIPAL 576 104,

Inventors:

#	Inventor's Name	Inventor's Address
1	SUNIL KUMAR AGRAWAL	MAHE, MANIPAL, MADHAV NAGAR, MANIPAL 576 119,
2	GANESA SUNDARARAJAN SUBRAMANIAN	MAHE, MANIPAL, MADHAV NAGAR, MANIPAL 576 119,
3	VIDYASAGAR	MAHE, MANIPAL, MADHAV NAGAR, MANIPAL 576 119,
4	NAYANABHIRAMA UDUPA	MAHE, MANIPAL, MADHAV NAGAR, MANIPAL 576 104,
5	PRAKASH SHETIYA	MAHE, MANIPAL, MADHAV NAGAR, MANIPAL 576 119,

PCT International Classification Number

A61K47/12

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA