Title of Invention	MUCOADHESIVE BUCCAL COMPOSITION CONTAINING NICOTINE USEFUL FOR SMOKING CESSATION AND A PROCESS FOR ITS PREPARATION
Abstract	The invention disclosed in this application relates to a mucoadhesive buccal composition useful for smoking cessation, which comprises hydrophilic polymers, nicotine, starch and excipients, the excipients having the property of controlling the release of nicotine, the resulting composition being provided with a backing membrane to facilitate unidirectional release of nicotine. This invention also relates to a process for the preparation of the said composition.

Title of Invention

MUCOADHESIVE BUCCAL COMPOSITION CONTAINING NICOTINE USEFUL FOR SMOKING CESSATION AND A PROCESS FOR ITS PREPARATION

Abstract

The invention disclosed in this application relates to a mucoadhesive buccal composition useful for smoking cessation, which comprises hydrophilic polymers, nicotine, starch and excipients, the excipients having the property of controlling the release of nicotine, the resulting composition being provided with a backing membrane to facilitate unidirectional release of nicotine. This invention also relates to a process for the preparation of the said composition.

Full Text	Field of the invention This invention relates to compositions comprising nicotine and methods for preparing said compositions being useful in drug therapy, preferably nicotine replacement, including tobacco substitution and smoking cessation. The invention relates to mucoadhesive buccal tablets containing nicotine for smoking cessation. Bioadhesion may be defined as the state in which two materials, at least one of which is of a biological nature, are held together for extended periods of time by interfacial forces. For drug delivery purposes, the term bioadhesion implies attachment of a drug carrier system to a specific biological location. If adhesive attachment is to a mucous coat, the phenomenon is referred to as mucoadhesion. Nicotine replacement therapy as a smoking cessation strategy has been successful in the past. (Therapy involves administration of nicotine in a non inhaled form to partially replace the nicotine that would otherwise been obtained from smoking. Nicotine without the carcinogenic and other adverse health consequences of the tars and gases that are concomitant to cigarette smoking gives the smoker a means to reduce nicotine withdrawal symptoms. The amount of nicotine administered is lower than that obtained from smoking tobacco but high enough to reduce withdrawal symptoms). Previous nicotine-containing compositions aiming towards the purpose of reducing nicotine craving for subjects wishing to stop their use of tobacco products include transdermal patch, nasal spray, chewing gum and inhalers. There are, however, subjects who may have cravings for higher doses of nicotine than those acceptable in applications of prior art and subjects that may not experience a decrease in other withdrawal symptoms because of unsatisfactory nicotine absorption. The most successful product which is used as a smoking substitute and/or as a smoking cessation aid and which is based on nicotine, is the chewing gum Nicorette.RTM. To date this product is the only form of nicotine replacement which has been approved by the Food and Drug Administration (FDA). Furthermore, it has to date been difficult to deliver nicotine in a profile mimicking the nicotine blood levels achieved by consistent smoking, to satisfy cravings for nicotine in people who are attempting to quit smoking, and thus, to provide greater protection against relapse than nicotine replacement therapies . Thus, absorption of nicotine in the use of currently marketed products and as disclosed in prior art of nicotine replacement therapies is not satisfactorily resembling the use of tobacco products, in particular smoking. With chewing gum nicotine replacement therapy for smoking cessation blood peak levels of nicotine is reached after 30 min. with venous blood nicotine levels about 1/3 to 2/3 of the levels attained when smoking (Br. Med. J. 1976, 1, 1043). A smoker will usually reach peak blood levels of nicotine 5-10 min. after starting smoking. Nicorette.RTM. has been on the market in about thirty countries for several years. In this chewing gum the nicotine is present in the form of a complex with an insoluble cation-exchanger (polacrilex) which is dispersed in a gum base. A buffering agent is also included in this composition. Patents related to this product are the U.S. Pat. Nos. 3,877,468, 3,901,248 and 3,845,217. Another product within this field is Favor.RTM. which was on the U.S. market for approximately 18 months but which had to be withdrawn as it did not fulfil the requirements set up by the Food and Drug Administration. This product, which is covered by the U.S. Pat. Nos. 4,284,089 and 4,800,903, is a nicotine inhalation device consisting of an elongated tube, in which a porous polymer plug including nicotine free base, is arranged. The main problem with this nicotine delivery system concerned the volatility of the nicotine free base which very rapidly disappeared from the system. It has been estimated that the shelf-life of the unrefrigerated vapor inhalor was approximately 1 month. A product which has not yet been approved by the health authorities but which is now undergoing clinical trials is a nicotine nasal solution of the type disclosed in the U.S. Pat. No. 4,579,858. This product is also based on the use of nicotine free base. Other compositions for nasal use is disclosed in the U.S. Pat. No. 4,655,231. According to this patent the composition is based on water soluble nicotine salts of organic acids, preferably oxalic acid. To the best of our knowledge no clinical studies have been performed with these compositions. It can be assumed, however, that when the salt dissociates in the nasal cavity, the acid moiety will increase the irritant sensation on the mucous membrane originating from the nicotine base formed. The main problems with products based on nicotine free base originate from the volatility of the nicotine, the irritant sensation of the mucous membranes, and the decomposition of nicotine in the presence of oxygen. To some extent these problems are also met with when nicotine is used in the form of a complex with an insoluble cation-exchanger resin as in the Nicorette.RTM. product. It should also be bom in mind that the nicotine is released from the nicotine resin only after extensive chewing. It is therefore desirable to provide improved compositions and methods which avoid the disadvantages of these conventional nicotine delivery devices and methods while providing an effective means for delivering nicotine for smoking cessation treatment, for reducing nicotine craving, and for treating other conditions responsive to nicotine therapy. We have surprisingly found that a rapid buccal absorption of nicotine is achieved through the use of nicotine containing formulations based on unidirectional release and mucoadhesive polymers . The formulations are intended for application in the oral cavity where upon the uptake of nicotine mainly takes place through the buccal mucosa. This is achieved with the help of mucoadhesive polymers which are biocompatible polymers with improved adhesive, muco-integrative, rheological, and barrier-modulating functions at epithelial surfaces. Drug absorption via the mucosal epithelium of the oral cavity is an established route of systemic drug delivery, which is especially useful if absorption after oral administration is incomplete or ineffective. The aim of this work was to develop mucoadhesive compositions of nicotine for buccal administration. Buccal tablets have the advantage of being cheap and easy to administer. Nicotine delivery by cigarettes is in the form of repeated, brief, high concentration arterial 'boluses' of nicotine. In contrast, transdermal nicotine delivers nicotine more slowly, with gradually rising and falling blood concentrations (i.e fewer peaks and troughs). The slow release characteristics explain, at least in part, why these nicotine replacement formulations do not stimulate all the pharmacological actions of nicotine desired by cigarette smokers, and do not provide satisfaction of smoking a cigarette. Rapid release formulations are therefore being developed. Transdermal delivery of nicotine has the capability of maintaining constant low levels of nicotine in the blood over an extended period of time. However, this steady-state nicotine delivery does not allow users to respond to 'breakthrough' cravings. These cravings, while usually brief, can be quite intense and are likely to be significant contributors to relapse. This suggests that smokers may need both a constant concentration of nicotine to relieve nicotine cravings and tobacco withdrawal symptoms (e.g. patch) as well as self administered, self titrated, faster acting preparation (e.g. gum, nasal spray or inhaler) for immediate relief of craving and withdrawal symptoms. Nicotine replacement therapy is available in a range of formulations Buccal tablets have the advantage of being cheap and easy to administer. When administering nicotine buccally from a chewing gum (i.e., by absorption of the drug through the highly vascularized buccal tissues of the mouth), a number of conditions are present which make it difficult to effectively deliver the nicotine in a controlled and therapeutically effective amount for a prolonged period of time (e.g., for periods greater than several minutes). The rate and vigor of chewing can vary greatly from patient to patient, thereby making controlled delivery of the nicotine nearly impossible. A further problem with chewing gums is that the patient's jaws become tired after extended chewing. This severely limit the time period for nicotine delivery. In addition, the action of saliva and swallowing by the patient effectively reduces the concentration of drug along the buccal membranes of the oral cavity and further causes much of the drug to be swallowed. In the case of nicotine, most of the absorbed drug is rendered inactive by the hepatic first-pass metabolism in the liver. Thus, there has been a need for an oral nicotine dosage form which is able to continuously deliver nicotine within the mouth to the buccal membranes (as rapid absorption is possible directly into systemic circulation) and which is relatively unaffected by the patient sucking and chewing on the device (the buccal tablet). Nicotine is generally in either free base or in salt form. Nicotine base is readily absorbed through skin and mucosal membranes. The nicotine base is the preferred form of nicotine for systemic transmucosal delivery since it is quickly absorbed through the oral mucosal membranes. Buccal compositions in the form of tablets (Tablets intended for application in the oral cavity where upon the uptake of nicotine mainly takes place through the buccal mucosa) have the advantage of being cheap and easy to administer. The buccal mucosa has a very good permeability and the drug enters directly into systemic circulation thereby avoiding first pass effect. Therefore a buccal tablet has the potential to provide rapid nicotine release to relieve cravings. These factors indicate a need of a new rapid release formulation along with controlled drug delivery systems for currently available drugs. Although there are new agents like antidepressants in development to reinforce the relief of smoking and stimulate brain receptors, there is no immediate panacea to restore the urge to smoke and relieve cravings. Ultimately it is nicotine which the smoker craves for. 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, new drug delivery systems can impart important advantages such as rapid release extending the duration of drug activity, which allows greater patient compliance owing to the elimination of multiple dosing schedules and reducing side effects due to optimization of blood concentration-time profiles. Buccal drug delivery devices(The formulations intended for application in the oral cavity where upon the uptake of nicotine mainly takes place through the buccal mucosa) offer many advantages over the conventional dosage forms or controlled release per oral delivery systems. Buccal route of drug delivery has gained interest in the recent past in the delivery of drugs that are susceptible to degradation in the gastrointestinal tract (GIT) or causes untoward effects if administered by conventional route. Hence buccal drug delivery systems increase patient compliance. It can be self administered so interruption or termination of treatment when necessary is possible. Due to high perfusion rate, nicotine could be expected to be absorbed rapidly from buccal area. So an attempt was made to design nicotine drug delivery systems using different mucoadhesive polymers. Hence, development of buccal drug delivery devices for nicotine would be an appropriate approach to overcome the breakthrough cravings experienced by smokers and patient noncompliance associated with other nicotine replacement products. Therefore it is the main objective of the present invention to provide a buccal drug delivery device for nicotine replacement therapy which overcomes the withdrawal symptoms, Gl side effects and patient non-compliance. Another objective of the present invention is to provide a tobacco substitute by way of a buccal drug delivery device, for use in for example smoking cessation and nicotine replacement therapy which provides the user with a satisfactory dose of nicotine so as to reduce tobacco withdrawal symptoms without causing an unacceptable local irritation. Yet another objective of the present invention is to provide a buccal delivery composition containing nicotine which releases the nicotine which releases nicotine at body temperature without the aid of salivary fluid or mechanical erosion, or a combination thereof and in which the formulation shows adhesiveness towards the body tissue in the oral cavity. Still another objective of the present invention to provide a method of preparing a drug delivery device containing nicotine containing composition for use in e.g. smoking cessation and nicotine replacement therapy which provides the user with a satisfactory dose of nicotine so as to reduce tobacco withdrawal symptoms without causing an unacceptable local irritation. The composition of the present invention releases nicotine at body temperature without the aid of salivary fluid or mechanical erosion, or a combination thereof and in which the formulation shows adhesiveness towards the body tissue in the oral cavity. Accordingly , the present invention provides a mucoadhesive buccal drug delivery device useful for smoking cessation, which comprises a matrix of hydrophilic polymers containing a mixture of nicotine and excipients which has the property of controlling the release of nicotine , the resulting matrix being provided with a coating of a backing membrane to facilitate unidirectional release of nicotine . According to another embodiment of the present invention there is provided a process for the preparation of mucoadhesive buccal composition useful for smoking cessation which comprises mixing blends of hydrophilic polymes, colloidal carriers, nicotine, starch and excipients. The excipients having the property of controlling the release of nicotine and adhering a backing membrane to the resulting composition to facilitate unidirectional release of nicotine. In a preferred embodiment of the invention Nicotine is adsorbed on colloidal carriers which has the property of adsorbing liquid before mixing with the excipients. Colloidal carriers such as silicon dioxide has good adsorbing property. Further such carriers have good tabletting properties, like improving the powder flow, imparting hardness to the tablet and is inert. Therefore, nicotine which is in liquid form, can be very well adsorbed in such carriers before mixing it with excipients One of ordinary skill in the art will appreciate that the components of the polymer can be varied to suit a particular purpose. For example, we have observed that one way of increasing (decreasing) the time it takes to release nicotine is by increasing (decreasing) the amount of starch and decreasing (increasing) the amount of hydrophilic polymers used. Furthermore, as will be appreciated by one of ordinary skill in the art following the teaching of the present invention, the composition can be sized, shaped and dosed to meet the needs of the particular treatment being undertaken. For example, the buccal bioadhesive composition may be constructed preferably, having 9.5 mm in diameter for the comfort of the patient, but made capable of delivering 5 mg of nicotine per day. A preferred method of manufacturing bioadhesive buccal composition of the present invention tablets is described below. The presently preferred method involves three steps as described below: 1. First step: Adsorbing nicotine on Colloidal carriers such as silicon dioxide. It is a good adsorbent. It is difficult to add small amount of liquid to a powder formulation without forming non uniform agglomerates in the composition. One approach is to dry up the liquid to a powder formulation without forming non uniform agglomerates in the composition. Therefore colloidal silicon dioxide was triturated in a dry mortar using pestle. To this nicotine was added gradually under trituration to get a uniform distribution.( 5mg of nicotine adsorbed on 100mg ofcolloidal silicon dioxide). 2. Second step: Formation of the composition Starch and nicotine adsorbed on colloidal silicon dioxide are mixed. Polymer HPMC is added to the mixture. Polymer HPMC may be mixed with Carbopol and added to the above mixture for getting good mucoadhesion and for releasing nicotine for a longer period of mucoadhesiveness. The resulting mixture is sieved through a sieve having aperture size, say in the range of 40-60 micron and then are added in geometric progression (starting with the smallest qty and adding same qty of other ingredient followed by the next higher qty of ingredient)and blended in a mortar with a pestle to obtain uniform mixing. 3. Third step: Tabletting the composition Since the composition of the present investigation can be administered easily in the form of tablets as well as such form are cheap, tablet forms are preferred. However it is to be noted that other forms can also be employed and are within the scope of the invention The step of preparing tablets is well established one For tableting the mixture obtained above is compressed by means of a rotative tableting machine equipped with punches preferably of 9.5 mm flat punches. The size is ideal as too big size would be obstructive and patient can feel its presence. Too small size may be difficult to place and distribute the required quantity of nicotine. The tablets are dedusted. 4. Fourth step The backing membrane is incorporated after the compression namely after forming the tablets. This backing membrane is adhered to one side of the tablet by gluing. The polymers which can be used for preparing the mucoadhesive buccal composition of the present invention may be selected from blends of hydrophilic polymers. As examples of such polymers mentioned is made to the blends of polymers like HPMC sodium alginate, Carbopol 934P, Chitosan, etc. Preferred mixture is the mixture of polymers containing HPMC and Carbopol, HPMC and sodium alginate, Sodium alginate and Chitosan . More preferable polymers, which can be used according to the present invention, are carbopol and hydroxypropyl methylcellulose. The backing membrane which can be used may be selected from polyisobutylene, acrylate adhesives or silicone adhesives. Once the device is adhered onto the buccal mucosa the device slowly releases the drug which permeates into the mucosa and finally reaches the systemic circulation. The amount of nicotine which can be incorporated into the buccal composition depends upon the desired release profile, the concentration of the drug required for achieving smoking cessation and the length of time that the drug has to be released for the treatment. In a preferred embodiment of the present invention, the mucoadhesive device may contain 5mg of nicotine, 10 mg of carbopol and 20mg of HPMC K4M besides other excipients to obtain the desired release characteristics like maintenance of required plasma concentration of nicotine for responding to break through cravings. The mucoadhesive buccal composition prepared as described above can be retained on the buccal mucosa for a period of upto 4-6 hours by the incorporation of saliva on the tablet side which comes in contact with buccal mucosa. The details of the invention are provided in the Example given below which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a liquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing . Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle. The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm2by rotating the pressure wheel of the machine. Once the tablets are formed polypropylene film is adheed into one side of the tablets as backing membrane using acrylate as an adhesive. First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a liquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing . Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic. The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle. The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm2by rotating the pressure wheel of the machine. Once the tablets are formed polypropylene film is adheed into one side of the tablets as backing membrane using acrylate as an adhesive. First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a liquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing . Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle. The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm by rotating the pressure wheel of the machine. Once the tablets are formed polypropylene film is adheed into one side of the tablets as backing membrane using acrylate as an adhesive. First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a liquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing . Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle. The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm2by rotating the pressure wheel of the machine. Once the tablets are formed polypropylene film is adheed into one side of the tablets as backing membrane using acrylate as an adhesive. First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a liquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing. Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle. The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm by rotating the pressure wheel of the machine. Once the tablets are formed polypropylene film is adheed into one side of the tablets as backing membrane using acrylate as an adhesive. First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a liquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing . Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic .The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle. The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm2by rotating the pressure wheel of the machine. Once the tablets are formed polypropylene film is adhered into one side of the tablets as backing membrane using acrylate as an adhesive. First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a liquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing . Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle. The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm2by rotating the pressure wheel of the machine. Once the tablets are formed polypropylene film is adheed into one side of the tablets as backing membrane using acrylate as an adhesive. First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a Hquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing . Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle. The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm2 by rotating the pressure wheel of the machine. Once the tablets are formed polypropylene film is adheed into one side of the tablets as backing membrane using acrylate as an adhesive. EXAMPLE 9 First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a liquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing . Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle. The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm2 by rotating the pressure wheel of the machine. Once the tablets are formed polypropylene film is adheed into one side of the tablets as backing membrane using acrylate as an adhesive. Table 1 depicts nine different formulations of bioadhesive tablets according to the invention. The amount of active ingredient, nicotine, was held constant at 5.0 mg. The nicotine dissolution rates of selected formulations were then studied. Fig 1-3 of the drawing accompanying this specification depicts the nicotine dissolution rate of tablets prepared by the process described in Examples 1 to 9 . During the dissolution process a general trend was observed in all the formulations i.e the polymer swelled: the more the polymer in the tablet the more the tablet swelled. Results notably differed among tablets depending on quality and quantity of mucoadhesive components. Fig: 1 of the drawing accompanying this specification shows the release profiles of nicotine from HPMC-sodium alginate tablets with varying ratios. It is observed at the release rate of nicotine from buccoadhesive tablets decreased with increasing concentration of HPMC. Composition of Example 1 containing only HPMC exhibited less drug release compared to the composition of Example 2 and Example 3 respectively. This may be due to the stability of HPMC polymer over a wide range of acid and alkaline conditions (Agarwal et al., 1999). In the tablets prepared with hydrophilic polymers such as HPMC, which do not have a covalently crosslinked structure, a gelatinous layer is formed on the surface of the tablets upon hydration. At higher concentrations, the linear polymer chains entangle to a greater degree resulting in virtual crosslinking and therefore formation of a stronger gel layer (Khan et al 1998). The tablets of Examplel released the drug at a controlled rate, controlled by the swelling of the polymer, followed by drug diffusion through swollen polymer and then 'further followed by slow erosion of the polymer. It has been reported that a higher concentration of HPMC provided more prolonged drug release through gelling and slow dissolution (Mumtaz et al., 1995). The ratio of the bioadhesive polymers HPMC and sodium alginate also altered the release rate. Sodium alginate is more hydrophilic than HPMC. It can swell rapidly, therefore decrease of sodium alginate content delays drug release. On contact of the tablets with water, sodium alginate rapidly hydrates and swells to form a gel layer over the tablet surface. Decreasing concentration of sodium alginate from Examples 2 & 3 decreased the release of nicotine. In case of formulation 4 the tablet formed a slippery surface due to over hydration leading to a rapid release. This could be attributed to rapid erosion of the resultant gel layer upon increasing sodium alginate concentration (Mohammed et al.,2003). The rate of penetration of the medium into the tablets and hence the rate of release of dissolved drug are a function of the amount of the hydrophilic sodium alginate dispersed throughout the matrix. Tablets with low alginate content hydrate less readily resulting in a slower release rate. Fig.2 shows the release profiles of nicotine from Carbopol and HPMC tablets with varying ratios. As the polymer fraction increased (HPMC) the dissolution of the drug decreased. Example 5 with 30%HPMC showed a retarded release which may be due to the gelling and slow dissolution of the polymer (Mumtaz et al, 1995). Formulation 7 released the drug at a faster rate due to higher carbopol. Carbopol is more hydrophilic than HPMC and if added in high ratios causes high release rates (Mikos et al., 1990). As the carbopol content increased, there was an increase in the amount of drug released. This phenomena can be explained by the swelling behaviour of the HPMC/Carbopol systems. These systems were swellable in water and a minimum time of l-2hr was needed for their complete swelling. Therefore during the early portion of the release kinetics the behaviour was almost similar for all the systems. Thus, the higher release rates for the tablets with a high carbopol content were an indication of the higher and faster swelling of carbopol which would lead to higher drug coefficients (Anlar et al., 1993). It has also been reported that Carbopol is more hydrophilic than HPMC; it can swell rapidly, therefore decrease of carbopol content delays the drug release (Ponchel et al 1987). Chitosan was chosen in the present study because its unique properties make it an excellent material for the development of controlled release buccal mucoadhesive devices. It is relatively cheap, biodegradable and bioerodible. Chitosan fiilfills the general requirements for auxiliary substances in the process of direct tabletting. At low concentration chitosan acts as a disintegrant (Nigalaye et al 1990) and at high concentration the gel forming property displayed a strong influence. Increasing the chitosan content decreased release rate of the drug (Miyazaki et al 1988). Fig.3 shows the release profiles of nicotine from Chitosan-sodium alginate tablets with varying ratios. When tablets came into contact with buffer, chitosan rapidly absorbed a large quantity of water swelled and then eroded gradually. Therefore, we assumed that the drug release from the tablets was probably governed first by dmg diffusion through the swollen gelled polymer. The Chitosan /alginate tablets of Example 9 having a higher alginate content displayed a faster release pattern compared to formulafion 8. This may be explained as a result of the diffusion of the release medium into the chitosan/alginate tablets, the water soluble polymer alginate present throughout the tablet, rapidly hydrated, swelled and dissolved leaching the chitosan matrix and allowing the drug to be rapidly released. In case of the composition of Example 8 with lower alginate content, chitosan swelled due to water uptake. This swelling and lack of erosion gave a retarding effect on nicotine drug release. The greater the amount of chitosan, the greater was the retarding effect, that is, high levels of chitosan retarded the drug release. This was attributed to the extent of gel formation and the hardness of the tablets (Sawayanagi et al., 1982). The differences observed in drug release as a function of the ratio of the two polymers were related to the differences in the water absorption and erosion behavior of the tablets in the release medium. The in vivo evaluation of the mucoadhesive buccal tablets was carried out The study was conducted in six healthy south Indian adult male smokers. The study was unblinded and conducted in age group between 25-40 years and weighing 50-60Kg. Subjects were confirmed to be in good health by physical examination, medical history and routine clinical tests. Exclusion criteria were any chronic illness or medication use and drug or alcohol abuse. Written consent was obtained from each subject. The study was approved by Hospital ethical committe. Approval number. KH/26-12/2002. The volunteers received written information about the aim of the study and informed consent was obtained from each of them. Each subject was required to abstain from smoking one day before the study. Subjects were restricted to the ward during the study period and were closely supervised at all times to insure that they did not smoke. Alcohol, caffeine and xanthine containing beverages were not permitted during the confinement period of the study. The volunteers were instructed to finish breakfast not later than 9.00a.m. Thirty mins later, the mucoadhesive tablet was administered. During the experiment the volunteers were allowed to drink water ad libitium from 30 mins after administration of the tablet. Bood samples were withdrawan from the cubital forearm vein before drug administration and then 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hrs after administration of the buccal tablet. Blood samples were collected in heparinised tubes, centrifuged and plasma was separated by centrifugation and frozen till further analysis. The nicotine concentration in plasma was quantitatively determined by HPLC. Calculation of pharmacokinetic parameters was done using P K Solution 2.0 software supplied by Summit Research Services Montrose, USA. which is based on non compartmental pharmacokinetic analysis. Fig. 4 shows the results of pharmacokinetic studies of mucoadhesive buccal tablet. Plasma concentration of nicotine was plotted against time after placing the device on the buccal mucosa . The mean plasma concentration-time profile after application of nicotine buccal tablets is shown in Fig:4. Trace amounts of nicotine (mean nicotine levels of 0.48ng/ml) were detected in the plasma before application of the buccal tablet. The presence of nicotine before system application (t=0hr) may be due to either passive exposure of volunteers to cigarette smoke in the environment or insufficient time for nicotine to clear from the body after an overnight abstention from cigarette smoking. Table 2: shows average nicotine concentration in six volunteers. Following the administration of the dosage form of the composition of Example 6 plasma nicotine concentrations were observed to rise rapidly in the first 2 hrs Table 2 Plasma concentrations of nicotine buccal tablet Peak plasma concentration (Cmax) of nicotine after administratin of the buccal dosage form was achieved in 2hrs (tmax) and found to be 16.8 ng/ml. It indicates rapid absorption of nicotine from buccal formulation. The results indicate that the buccal dosage form is potentially useful clinically in nicotine replacement therapy. The buccal mucosa may be a more favorable site for absorption of nicotine. Non keratinised and strongly supplied with blood, with a dense capillary network, it constitutes a relatively large drug absorption area. Drug can thus reach the systemic circulation directly through capillary vessels, by-passing the first pass metabolism in the intestines and liver or avoiding inactivation in the stomach (Harris et al, 1992). This in turn contributes to higher bioavailability parameters after administration of a smaller dose of drug. C max .peak concentration observed during the dosing period. tmax - time to reach the peak concentration (Cmax)- AUC(o-24) - area under the plasma concentration time curves. t1/2 - eUminationhalf hfe ket . eUmination rate constant Area under the concentration-time curve AUC((0-24) was found to be 82.4 ± 24.0 ng/ml for 5 mg of buccal tablet. The high Cmax value of buccal tablets indicates rapid absorption into systemic circulation (tmax =2 hrs) which can be readily used in smoking cessation for break through cravings. The half life of nicotine in buccal tablets was found to be 2.61 hrs and it necessitates frequent dosing. The elimination rate constant of nicotine buccal tablet (0.27 hf') indicates rapid clearance. Buccal route of drug delivery has gained interest in the recent past in the delivery of drugs that are susceptible to degradation in the GIT or causes untoward effects if administered by conventional route. Due to high perfusion rate, nicotine could be expected to be absorbed rapidly from buccal area and also it bypasses the GIT environment. So an attempt was made to design nicotine drug delivery systems using different mucoadhesive polymers. When compared with the gum (Cmax 11.9 ng/ml), our buccal tablet showed a peak plasma concentration of 16.1 ng/ml which indicates better bioavailability. Since the buccal tablet remains stationary at the buccal mucosa, it is in constant contact with the buccal mucosa. Hence it is able to provide better bioavailability compared to the gum. Also the compliance rate of the gum is less due to undesirable taste and gastrointestinal adverse effects. The mucoadhesive buccal tablets showed better compliance in human volunteers. Advantages of the invention 1. The composition overcomes the severe break through cravings experienced as withrawal symptoms by heavy smokers. 2. The composition can be self administered. The therapy can be discontinued when desired. And hence can be manipulated to suit the users need. 3. The release of nicotine from the composition is rapid. 4. The composition is convenient and quantitative on the basis of the amount of substance (drug) to be delivered into systemic circulation through buccal mucosa. 5. The composition is user friendly. We Claim 1. A mucoadhesive buccal composition useful for smoking cessation, which comprises hydrophilic polymers, nicotine, starch, colloidal carriers and excipients, the excipients having the property of controlling the release of nicotine, the resulting composition being provided with a backing membrane to facilitate unidirectional release of nicotine. 2. The mucoadhesive buccal composition as claimed in claim 1 wherein nicotine is adsorbed on colloidal carriers which has the property of adsorbing liquid before mixing with the excipients. 3. The mucoadhesive buccal composition as claimed in claim 2 wherein the colloidal carriers such as silica, or silicon dioxide (silicium dioxide), is used. 4. The mucoadhesive composition as claimed in claims 1 to 3 wherein hydrophilic polymers used are selected from a water insoluble, water-swellable cross-linked polycarboyllic polymer, and a water soluble polymer. 5. The mucoadhesive buccal composition as claimed in claim 4 wherein the polymer used is selected from hydroxypropylmethyl cellulose carbopol and other water swellable forms of cellulose, carbopol and other water-swellable forms of cellulose and polymers and the like. 6. The mucoahesive buccal composition as claimed in claims 1 to 5, wherein the ratio of the polymers used ranges from 5:10 to 5:30. 7. The mucoadhesive buccal composition as claimed in claims 1 to 6 wherein the concentration of the polymers used ranges from 10-40%. 8. The mucoadhesive buccal composition as claimed in claims 1 to 7 wherein the excipients used is selected from magnesium stearate, stearic acid and talc. 9. The mucoadhesive buccal composition as claimed in claims 1 to 8 wherein the backing membrane is selected from pressure sensitive acrylate adhesives. 10. The mucoadhesive buccal composition as claimed in claims 1 to 9 wherein the amount of nicotine used in the composition is 5mg. 11. A process for the preparation of mucoadhesive buccal composition useful for smoking cessation which comprises, adsorbing nicotine on colloidal carrier-silicon dioxide, mixing hydrophilic polymers, starch and excipients, the excipients having the property of controlling the release of nicotine, the resulting mixture compressed on a tablet compression machine and tablet formed being provided with a backing membrane to facilitate unidirectional release of nicotine. 12. The process as claimed in claim 11 wherein Nicotine is adsorbed on colloidal carriers which has the property of adsorbing liquid before mixing with the excipients. 13. The process as claimed in claims 11 & 12 wherein the colloidal carriers such as silicon dioxide are used. 14. The process as claimed in claims 11 to 13 wherein hydrophilic polymers used are selected from a water insoluble, water swellable cross linked polycarboxylic polymer, and a water soluble polymer. 15. The process as claimed in claim 14 wherein the polymer used is selected from HPMC or hydroxypropylmethyl cellulose and other water swellable forms of cellulose and polymers and the like. 16. The process as claimed in claims 11 to 15 wherein the excipients used are selected from magnesium stearate, stearic acid and talc. 17. The process as claimed in claims 11 to 16wherein the backing membrane is selected from polyisobutylene, acrylate adhesives or silicone adhesives. 18. The process as claimed in claims 11 to 17 wherein the amount of nicotine used in the composition is 5mg. 19. The mucoadhesive buccal composition useful for smoking cessation substantially as herein described with reference to the Examples 1 to 9. 20. The process for the preparation of mucoadhesive buccal composition useful for smoking cessation substantially as herein described with reference to the examples 1 to 9.

Full Text

Field of the invention
This invention relates to compositions comprising nicotine and methods for preparing said compositions being useful in drug therapy, preferably nicotine replacement, including tobacco substitution and smoking cessation.
The invention relates to mucoadhesive buccal tablets containing nicotine for smoking cessation. Bioadhesion may be defined as the state in which two materials, at least one of which is of a biological nature, are held together for extended periods of time by interfacial forces. For drug delivery purposes, the term bioadhesion implies attachment of a drug carrier system to a specific biological location. If adhesive attachment is to a mucous coat, the phenomenon is referred to as mucoadhesion.
Nicotine replacement therapy as a smoking cessation strategy has been successful in the past. (Therapy involves administration of nicotine in a non inhaled form to partially replace the nicotine that would otherwise been obtained from smoking. Nicotine without the carcinogenic and other adverse health consequences of the tars and gases that are concomitant to cigarette smoking gives the smoker a means to reduce nicotine withdrawal symptoms. The amount of nicotine administered is lower than that obtained from smoking tobacco but high enough to reduce withdrawal symptoms).
Previous nicotine-containing compositions aiming towards the purpose of reducing nicotine craving for subjects wishing to stop their use of tobacco products include transdermal patch, nasal spray, chewing gum and inhalers.
There are, however, subjects who may have cravings for higher doses of nicotine than those acceptable in applications of prior art and subjects that may not experience a decrease in other withdrawal symptoms because of unsatisfactory nicotine absorption.
The most successful product which is used as a smoking substitute and/or as a smoking cessation aid and which is based on nicotine, is the chewing gum Nicorette.RTM. To date this product is the only form of nicotine replacement which has been approved by the Food and Drug Administration (FDA). Furthermore, it has to date been difficult to deliver nicotine in a profile mimicking the nicotine blood levels achieved by consistent smoking, to satisfy cravings for nicotine in people who are attempting to quit smoking, and thus, to provide greater

protection against relapse than nicotine replacement therapies . Thus, absorption of nicotine in the use of currently marketed products and as disclosed in prior art of nicotine replacement therapies is not satisfactorily resembling the use of tobacco products, in particular smoking. With chewing gum nicotine replacement therapy for smoking cessation blood peak levels of nicotine is reached after 30 min. with venous blood nicotine levels about 1/3 to 2/3 of the levels attained when smoking (Br. Med. J. 1976, 1, 1043). A smoker will usually reach peak blood levels of nicotine 5-10 min. after starting smoking.
Nicorette.RTM. has been on the market in about thirty countries for several years. In this chewing gum the nicotine is present in the form of a complex with an insoluble cation-exchanger (polacrilex) which is dispersed in a gum base. A buffering agent is also included in this composition. Patents related to this product are the U.S. Pat. Nos. 3,877,468, 3,901,248 and 3,845,217.
Another product within this field is Favor.RTM. which was on the U.S. market for approximately 18 months but which had to be withdrawn as it did not fulfil the requirements set up by the Food and Drug Administration. This product, which is covered by the U.S. Pat. Nos. 4,284,089 and 4,800,903, is a nicotine inhalation device consisting of an elongated tube, in which a porous polymer plug including nicotine free base, is arranged. The main problem with this nicotine delivery system concerned the volatility of the nicotine free base which very rapidly disappeared from the system. It has been estimated that the shelf-life of the unrefrigerated vapor inhalor was approximately 1 month.
A product which has not yet been approved by the health authorities but which is now undergoing clinical trials is a nicotine nasal solution of the type disclosed in the U.S. Pat. No. 4,579,858. This product is also based on the use of nicotine free base.
Other compositions for nasal use is disclosed in the U.S. Pat. No. 4,655,231. According to this patent the composition is based on water soluble nicotine salts of organic acids, preferably oxalic acid. To the best of our knowledge no clinical studies have been performed with these compositions. It can be assumed, however, that when the salt dissociates in the nasal cavity, the acid moiety will increase the irritant sensation on the mucous membrane originating from the nicotine base formed.

The main problems with products based on nicotine free base originate from the volatility of the nicotine, the irritant sensation of the mucous membranes, and the decomposition of nicotine in the presence of oxygen. To some extent these problems are also met with when nicotine is used in the form of a complex with an insoluble cation-exchanger resin as in the Nicorette.RTM. product. It should also be bom in mind that the nicotine is released from the nicotine resin only after extensive chewing.
It is therefore desirable to provide improved compositions and methods which avoid the disadvantages of these conventional nicotine delivery devices and methods while providing an effective means for delivering nicotine for smoking cessation treatment, for reducing nicotine craving, and for treating other conditions responsive to nicotine therapy.
We have surprisingly found that a rapid buccal absorption of nicotine is achieved through the use of nicotine containing formulations based on unidirectional release and mucoadhesive polymers . The formulations are intended for application in the oral cavity where upon the uptake of nicotine mainly takes place through the buccal mucosa. This is achieved with the help of mucoadhesive polymers which are biocompatible polymers with improved adhesive, muco-integrative, rheological, and barrier-modulating functions at epithelial surfaces.
Drug absorption via the mucosal epithelium of the oral cavity is an established route of systemic drug delivery, which is especially useful if absorption after oral administration is incomplete or ineffective.
The aim of this work was to develop mucoadhesive compositions of nicotine for buccal administration. Buccal tablets have the advantage of being cheap and easy to administer.
Nicotine delivery by cigarettes is in the form of repeated, brief, high concentration arterial 'boluses' of nicotine. In contrast, transdermal nicotine delivers nicotine more slowly, with gradually rising and falling blood concentrations (i.e fewer peaks and troughs). The slow release characteristics explain, at least in part, why these nicotine replacement formulations do not stimulate all the pharmacological actions of nicotine desired by cigarette smokers, and do

not provide satisfaction of smoking a cigarette. Rapid release formulations are therefore being developed.
Transdermal delivery of nicotine has the capability of maintaining constant low levels of nicotine in the blood over an extended period of time. However, this steady-state nicotine delivery does not allow users to respond to 'breakthrough' cravings. These cravings, while usually brief, can be quite intense and are likely to be significant contributors to relapse. This suggests that smokers may need both a constant concentration of nicotine to relieve nicotine cravings and tobacco withdrawal symptoms (e.g. patch) as well as self administered, self titrated, faster acting preparation (e.g. gum, nasal spray or inhaler) for immediate relief of craving and withdrawal symptoms. Nicotine replacement therapy is available in a range of formulations Buccal tablets have the advantage of being cheap and easy to administer.
When administering nicotine buccally from a chewing gum (i.e., by absorption of the drug through the highly vascularized buccal tissues of the mouth), a number of conditions are present which make it difficult to effectively deliver the nicotine in a controlled and therapeutically effective amount for a prolonged period of time (e.g., for periods greater than several minutes). The rate and vigor of chewing can vary greatly from patient to patient, thereby making controlled delivery of the nicotine nearly impossible. A further problem with chewing gums is that the patient's jaws become tired after extended chewing. This severely limit the time period for nicotine delivery.
In addition, the action of saliva and swallowing by the patient effectively reduces the concentration of drug along the buccal membranes of the oral cavity and further causes much of the drug to be swallowed. In the case of nicotine, most of the absorbed drug is rendered inactive by the hepatic first-pass metabolism in the liver.
Thus, there has been a need for an oral nicotine dosage form which is able to continuously deliver nicotine within the mouth to the buccal membranes (as rapid absorption is possible directly into systemic circulation) and which is relatively unaffected by the patient sucking and chewing on the device (the buccal tablet). Nicotine is generally in either free base or in salt form. Nicotine base is readily absorbed through skin and mucosal membranes. The nicotine base is the preferred form of nicotine for systemic transmucosal delivery since it is quickly absorbed through the oral mucosal membranes.
Buccal compositions in the form of tablets (Tablets intended for application in the oral cavity where upon the uptake of nicotine mainly takes place through the buccal mucosa) have

the advantage of being cheap and easy to administer. The buccal mucosa has a very good permeability and the drug enters directly into systemic circulation thereby avoiding first pass effect. Therefore a buccal tablet has the potential to provide rapid nicotine release to relieve cravings.
These factors indicate a need of a new rapid release formulation along with controlled drug delivery systems for currently available drugs. Although there are new agents like antidepressants in development to reinforce the relief of smoking and stimulate brain receptors, there is no immediate panacea to restore the urge to smoke and relieve cravings. Ultimately it is nicotine which the smoker craves for.
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, new drug delivery systems can impart important advantages such as rapid release extending the duration of drug activity, which allows greater patient compliance owing to the elimination of multiple dosing schedules and reducing side effects due to optimization of blood concentration-time profiles.
Buccal drug delivery devices(The formulations intended for application in the oral cavity where upon the uptake of nicotine mainly takes place through the buccal mucosa) offer many advantages over the conventional dosage forms or controlled release per oral delivery systems. Buccal route of drug delivery has gained interest in the recent past in the delivery of drugs that are susceptible to degradation in the gastrointestinal tract (GIT) or causes untoward effects if administered by conventional route. Hence buccal drug delivery systems increase patient compliance. It can be self administered so interruption or termination of treatment when necessary is possible.
Due to high perfusion rate, nicotine could be expected to be absorbed rapidly from buccal area. So an attempt was made to design nicotine drug delivery systems using different mucoadhesive polymers.

Hence, development of buccal drug delivery devices for nicotine would be an appropriate approach to overcome the breakthrough cravings experienced by smokers and patient noncompliance associated with other nicotine replacement products.
Therefore it is the main objective of the present invention to provide a buccal drug delivery device for nicotine replacement therapy which overcomes the withdrawal symptoms, Gl side effects and patient non-compliance.
Another objective of the present invention is to provide a tobacco substitute by way of a buccal drug delivery device, for use in for example smoking cessation and nicotine replacement therapy which provides the user with a satisfactory dose of nicotine so as to reduce tobacco withdrawal symptoms without causing an unacceptable local irritation.
Yet another objective of the present invention is to provide a buccal delivery composition containing nicotine which releases the nicotine which releases nicotine at body temperature without the aid of salivary fluid or mechanical erosion, or a combination thereof and in which the formulation shows adhesiveness towards the body tissue in the oral cavity.
Still another objective of the present invention to provide a method of preparing a drug delivery device containing nicotine containing composition for use in e.g. smoking cessation and nicotine replacement therapy which provides the user with a satisfactory dose of nicotine so as to reduce tobacco withdrawal symptoms without causing an unacceptable local irritation.
The composition of the present invention releases nicotine at body temperature without the aid of salivary fluid or mechanical erosion, or a combination thereof and in which the formulation shows adhesiveness towards the body tissue in the oral cavity.
Accordingly , the present invention provides a mucoadhesive buccal drug delivery device useful for smoking cessation, which comprises a matrix of hydrophilic polymers containing a mixture of nicotine and excipients which has the property of controlling the release of nicotine , the resulting matrix being provided with a coating of a backing membrane to facilitate unidirectional release of nicotine .

According to another embodiment of the present invention there is provided a process for the preparation of mucoadhesive buccal composition useful for smoking cessation which comprises mixing blends of hydrophilic polymes, colloidal carriers, nicotine, starch and excipients. The excipients having the property of controlling the release of nicotine and adhering a backing membrane to the resulting composition to facilitate unidirectional release of nicotine.
In a preferred embodiment of the invention Nicotine is adsorbed on colloidal carriers which has the property of adsorbing liquid before mixing with the excipients. Colloidal carriers such as silicon dioxide has good adsorbing property. Further such carriers have good tabletting properties, like improving the powder flow, imparting hardness to the tablet and is inert. Therefore, nicotine which is in liquid form, can be very well adsorbed in such carriers before mixing it with excipients
One of ordinary skill in the art will appreciate that the components of the polymer can be varied to suit a particular purpose. For example, we have observed that one way of increasing (decreasing) the time it takes to release nicotine is by increasing (decreasing) the amount of starch and decreasing (increasing) the amount of hydrophilic polymers used.
Furthermore, as will be appreciated by one of ordinary skill in the art following the teaching of the present invention, the composition can be sized, shaped and dosed to meet the needs of the particular treatment being undertaken. For example, the buccal bioadhesive composition may be constructed preferably, having 9.5 mm in diameter for the comfort of the patient, but made capable of delivering 5 mg of nicotine per day.
A preferred method of manufacturing bioadhesive buccal composition of the present invention tablets is described below. The presently preferred method involves three steps as described below:
1. First step: Adsorbing nicotine on Colloidal carriers such as silicon dioxide. It is a good adsorbent. It is difficult to add small amount of liquid to a powder formulation without forming non uniform agglomerates in the composition. One approach is to dry up the liquid to a powder formulation without forming non uniform agglomerates in the composition. Therefore colloidal silicon dioxide was triturated in a dry mortar using pestle. To this nicotine was added gradually under trituration to get a uniform distribution.( 5mg of nicotine adsorbed on 100mg ofcolloidal silicon dioxide).

2. Second step: Formation of the composition
Starch and nicotine adsorbed on colloidal silicon dioxide are mixed. Polymer HPMC is added to the mixture. Polymer HPMC may be mixed with Carbopol and added to the above mixture for getting good mucoadhesion and for releasing nicotine for a longer period of mucoadhesiveness. The resulting mixture is sieved through a sieve having aperture size, say in the range of 40-60 micron and then are added in geometric progression (starting with the smallest qty and adding same qty of other ingredient followed by the next higher qty of ingredient)and blended in a mortar with a pestle to obtain uniform mixing.
3. Third step: Tabletting the composition
Since the composition of the present investigation can be administered easily in the form of tablets as well as such form are cheap, tablet forms are preferred. However it is to be noted that other forms can also be employed and are within the scope of the invention The step of preparing tablets is well established one
For tableting the mixture obtained above is compressed by means of a rotative tableting machine equipped with punches preferably of 9.5 mm flat punches. The size is ideal as too big size would be obstructive and patient can feel its presence. Too small size may be difficult to place and distribute the required quantity of nicotine. The tablets are dedusted.
4. Fourth step
The backing membrane is incorporated after the compression namely after forming the tablets. This backing membrane is adhered to one side of the tablet by gluing. The polymers which can be used for preparing the mucoadhesive buccal composition of the present invention may be selected from blends of hydrophilic polymers. As examples of such polymers mentioned is made to the blends of polymers like HPMC sodium alginate, Carbopol 934P, Chitosan, etc. Preferred mixture is the mixture of polymers containing HPMC and Carbopol, HPMC and sodium alginate, Sodium alginate and Chitosan . More preferable polymers, which can be used according to the present invention, are carbopol and hydroxypropyl methylcellulose.
The backing membrane which can be used may be selected from polyisobutylene, acrylate adhesives or silicone adhesives. Once the device is adhered onto the buccal mucosa

the device slowly releases the drug which permeates into the mucosa and finally reaches the systemic circulation.
The amount of nicotine which can be incorporated into the buccal composition depends upon the desired release profile, the concentration of the drug required for achieving smoking cessation and the length of time that the drug has to be released for the treatment.
In a preferred embodiment of the present invention, the mucoadhesive device may contain 5mg of nicotine, 10 mg of carbopol and 20mg of HPMC K4M besides other excipients to obtain the desired release characteristics like maintenance of required plasma concentration of nicotine for responding to break through cravings.
The mucoadhesive buccal composition prepared as described above can be retained on the
buccal mucosa for a period of upto 4-6 hours by the incorporation of saliva on the tablet side
which comes in contact with buccal mucosa.
The details of the invention are provided in the Example given below which are given to
illustrate the invention only and therefore should not be construed to limit the scope of the
invention

First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a liquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing . Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic

The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle. The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm2by rotating the pressure wheel of the machine.
Once the tablets are formed polypropylene film is adheed into one side of the tablets as backing membrane using acrylate as an adhesive.

First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a liquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing . Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic.
The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle. The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm2by rotating the pressure wheel of the machine.
Once the tablets are formed polypropylene film is adheed into one side of the tablets as backing membrane using acrylate as an adhesive.

First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a liquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing . Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic
The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle. The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm by rotating the pressure wheel of the machine.
Once the tablets are formed polypropylene film is adheed into one side of the tablets as backing membrane using acrylate as an adhesive.

First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a liquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing . Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic
The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle. The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm2by rotating the pressure wheel of the machine.
Once the tablets are formed polypropylene film is adheed into one side of the tablets as backing membrane using acrylate as an adhesive.

First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a liquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was

titurated for 5 minutes to ensure uniform mixing. Magnesium stearate was mixed for 1 minute
at the end as it is hydrophobic
The resulting mixture is now ready for compression into tablets. Therefore the mixture was
compressed in a compression machine provided with punch and die. 100mg of the mixture was
fed into the die cavity of the compression machine and the machine was rotated for 1 cycle.
The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm by rotating the
pressure wheel of the machine.
Once the tablets are formed polypropylene film is adheed into one side of the tablets as
backing membrane using acrylate as an adhesive.

First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a liquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing . Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic
.The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle. The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm2by rotating the pressure wheel of the machine.
Once the tablets are formed polypropylene film is adhered into one side of the tablets as backing membrane using acrylate as an adhesive.

First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a liquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing . Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic
The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle. The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm2by rotating the pressure wheel of the machine.
Once the tablets are formed polypropylene film is adheed into one side of the tablets as backing membrane using acrylate as an adhesive.

First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a Hquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing . Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic
The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle. The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm2 by rotating the pressure wheel of the machine.
Once the tablets are formed polypropylene film is adheed into one side of the tablets as backing membrane using acrylate as an adhesive.
EXAMPLE 9

First all the above ingredients, except nicotine were weighed kept aside. Nicotine being a liquid is adsorbed on silicon dioxide. To this the other ingredients except magnesium stearate was added by geometrical dilution (By this method the ingredient with smallest quantity is added followed by same quantity of the next highest ingredient). The resulting blend was titurated for 5 minutes to ensure uniform mixing . Magnesium stearate was mixed for 1 minute at the end as it is hydrophobic
The resulting mixture is now ready for compression into tablets. Therefore the mixture was compressed in a compression machine provided with punch and die. 100mg of the mixture was fed into the die cavity of the compression machine and the machine was rotated for 1 cycle.

The blend got compressed into tablets. The hardness was adjusted to 2-3kg/cm2 by rotating the
pressure wheel of the machine.
Once the tablets are formed polypropylene film is adheed into one side of the tablets as
backing membrane using acrylate as an adhesive.
Table 1 depicts nine different formulations of bioadhesive tablets according to the invention.
The amount of active ingredient, nicotine, was held constant at 5.0 mg.

The nicotine dissolution rates of selected formulations were then studied. Fig 1-3 of the drawing accompanying this specification depicts the nicotine dissolution rate of tablets prepared by the process described in Examples 1 to 9 .
During the dissolution process a general trend was observed in all the formulations i.e the polymer swelled: the more the polymer in the tablet the more the tablet swelled. Results

notably differed among tablets depending on quality and quantity of mucoadhesive components.
Fig: 1 of the drawing accompanying this specification shows the release profiles of nicotine from HPMC-sodium alginate tablets with varying ratios.
It is observed at the release rate of nicotine from buccoadhesive tablets decreased with increasing concentration of HPMC. Composition of Example 1 containing only HPMC exhibited less drug release compared to the composition of Example 2 and Example 3 respectively. This may be due to the stability of HPMC polymer over a wide range of acid and alkaline conditions (Agarwal et al., 1999).
In the tablets prepared with hydrophilic polymers such as HPMC, which do not have a covalently crosslinked structure, a gelatinous layer is formed on the surface of the tablets upon hydration. At higher concentrations, the linear polymer chains entangle to a greater degree resulting in virtual crosslinking and therefore formation of a stronger gel layer (Khan et al 1998).
The tablets of Examplel released the drug at a controlled rate, controlled by the swelling of the polymer, followed by drug diffusion through swollen polymer and then 'further followed by slow erosion of the polymer.
It has been reported that a higher concentration of HPMC provided more prolonged drug release through gelling and slow dissolution (Mumtaz et al., 1995).
The ratio of the bioadhesive polymers HPMC and sodium alginate also altered the release rate. Sodium alginate is more hydrophilic than HPMC. It can swell rapidly, therefore decrease of sodium alginate content delays drug release.
On contact of the tablets with water, sodium alginate rapidly hydrates and swells to form a gel layer over the tablet surface. Decreasing concentration of sodium alginate from Examples 2 & 3 decreased the release of nicotine. In case of formulation 4 the tablet formed a slippery surface due to over hydration leading to a rapid release. This could be attributed to rapid erosion of the resultant gel layer upon increasing sodium alginate concentration (Mohammed et al.,2003).
The rate of penetration of the medium into the tablets and hence the rate of release of dissolved drug are a function of the amount of the hydrophilic sodium alginate dispersed throughout the

matrix. Tablets with low alginate content hydrate less readily resulting in a slower release rate.
Fig.2 shows the release profiles of nicotine from Carbopol and HPMC tablets with varying ratios. As the polymer fraction increased (HPMC) the dissolution of the drug decreased. Example 5 with 30%HPMC showed a retarded release which may be due to the gelling and slow dissolution of the polymer (Mumtaz et al, 1995).
Formulation 7 released the drug at a faster rate due to higher carbopol. Carbopol is more hydrophilic than HPMC and if added in high ratios causes high release rates (Mikos et al., 1990). As the carbopol content increased, there was an increase in the amount of drug released. This phenomena can be explained by the swelling behaviour of the HPMC/Carbopol systems. These systems were swellable in water and a minimum time of l-2hr was needed for their complete swelling. Therefore during the early portion of the release kinetics the behaviour was almost similar for all the systems. Thus, the higher release rates for the tablets with a high carbopol content were an indication of the higher and faster swelling of carbopol which would lead to higher drug coefficients (Anlar et al., 1993).
It has also been reported that Carbopol is more hydrophilic than HPMC; it can swell rapidly, therefore decrease of carbopol content delays the drug release (Ponchel et al 1987).
Chitosan was chosen in the present study because its unique properties make it an excellent material for the development of controlled release buccal mucoadhesive devices. It is relatively cheap, biodegradable and bioerodible. Chitosan fiilfills the general requirements for auxiliary substances in the process of direct tabletting.
At low concentration chitosan acts as a disintegrant (Nigalaye et al 1990) and at high concentration the gel forming property displayed a strong influence. Increasing the chitosan content decreased release rate of the drug (Miyazaki et al 1988).
Fig.3 shows the release profiles of nicotine from Chitosan-sodium alginate tablets with varying ratios.
When tablets came into contact with buffer, chitosan rapidly absorbed a large quantity of water swelled and then eroded gradually. Therefore, we assumed that the drug release from the tablets was probably governed first by dmg diffusion through the swollen gelled polymer.
The Chitosan /alginate tablets of Example 9 having a higher alginate content displayed a faster release pattern compared to formulafion 8. This may be explained as a result of the diffusion of

the release medium into the chitosan/alginate tablets, the water soluble polymer alginate present throughout the tablet, rapidly hydrated, swelled and dissolved leaching the chitosan matrix and allowing the drug to be rapidly released.
In case of the composition of Example 8 with lower alginate content, chitosan swelled due to water uptake. This swelling and lack of erosion gave a retarding effect on nicotine drug release. The greater the amount of chitosan, the greater was the retarding effect, that is, high levels of chitosan retarded the drug release. This was attributed to the extent of gel formation and the hardness of the tablets (Sawayanagi et al., 1982).
The differences observed in drug release as a function of the ratio of the two polymers were related to the differences in the water absorption and erosion behavior of the tablets in the release medium.
The in vivo evaluation of the mucoadhesive buccal tablets was carried out The study was conducted in six healthy south Indian adult male smokers. The study was unblinded and conducted in age group between 25-40 years and weighing 50-60Kg. Subjects were confirmed to be in good health by physical examination, medical history and routine clinical tests. Exclusion criteria were any chronic illness or medication use and drug or alcohol abuse.
Written consent was obtained from each subject. The study was approved by Hospital ethical committe. Approval number. KH/26-12/2002. The volunteers received written information about the aim of the study and informed consent was obtained from each of them. Each subject was required to abstain from smoking one day before the study. Subjects were restricted to the ward during the study period and were closely supervised at all times to insure that they did not smoke. Alcohol, caffeine and xanthine containing beverages were not permitted during the confinement period of the study. The volunteers were instructed to finish breakfast not later than 9.00a.m. Thirty mins later, the mucoadhesive tablet was administered. During the experiment the volunteers were allowed to drink water ad libitium from 30 mins after administration of the tablet.
Bood samples were withdrawan from the cubital forearm vein before drug administration and then 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hrs after administration of the buccal tablet. Blood samples were collected in heparinised tubes, centrifuged and plasma was separated by centrifugation and frozen till further analysis. The nicotine concentration in plasma was quantitatively determined by HPLC. Calculation of pharmacokinetic parameters was done using P K Solution

2.0 software supplied by Summit Research Services Montrose, USA. which is based on non compartmental pharmacokinetic analysis.
Fig. 4 shows the results of pharmacokinetic studies of mucoadhesive buccal tablet. Plasma concentration of nicotine was plotted against time after placing the device on the buccal mucosa .
The mean plasma concentration-time profile after application of nicotine buccal tablets is shown in Fig:4. Trace amounts of nicotine (mean nicotine levels of 0.48ng/ml) were detected in the plasma before application of the buccal tablet. The presence of nicotine before system application (t=0hr) may be due to either passive exposure of volunteers to cigarette smoke in the environment or insufficient time for nicotine to clear from the body after an overnight abstention from cigarette smoking. Table 2: shows average nicotine concentration in six volunteers.
Following the administration of the dosage form of the composition of Example 6 plasma nicotine concentrations were observed to rise rapidly in the first 2 hrs
Table 2 Plasma concentrations of nicotine buccal tablet

Peak plasma concentration (Cmax) of nicotine after administratin of the buccal dosage form was achieved in 2hrs (tmax) and found to be 16.8 ng/ml. It indicates rapid absorption of nicotine from buccal formulation.
The results indicate that the buccal dosage form is potentially useful clinically in nicotine replacement therapy.
The buccal mucosa may be a more favorable site for absorption of nicotine. Non keratinised and strongly supplied with blood, with a dense capillary network, it constitutes a relatively large drug absorption area. Drug can thus reach the systemic circulation directly through capillary vessels, by-passing the first pass metabolism in the intestines and liver or avoiding inactivation in the stomach (Harris et al, 1992). This in turn contributes to higher bioavailability parameters after administration of a smaller dose of drug.

C max .peak concentration observed during the dosing period.
tmax - time to reach the peak concentration (Cmax)-
AUC(o-24) - area under the plasma concentration time curves.
t1/2 - eUminationhalf hfe
ket . eUmination rate constant
Area under the concentration-time curve AUC((0-24) was found to be 82.4 ± 24.0 ng/ml for 5 mg of buccal tablet. The high Cmax value of buccal tablets indicates rapid absorption into systemic circulation (tmax =2 hrs) which can be readily used in smoking cessation for break through cravings. The half life of nicotine in buccal tablets was found to be 2.61 hrs and it necessitates frequent dosing. The elimination rate constant of nicotine buccal tablet (0.27 hf') indicates rapid clearance.
Buccal route of drug delivery has gained interest in the recent past in the delivery of drugs that are susceptible to degradation in the GIT or causes untoward effects if administered by conventional route. Due to high perfusion rate, nicotine could be expected to be absorbed rapidly from buccal area and also it bypasses the GIT environment. So an attempt was made to design nicotine drug delivery systems using different mucoadhesive polymers. When compared with the gum (Cmax 11.9 ng/ml), our buccal tablet showed a peak plasma concentration of 16.1 ng/ml which indicates better bioavailability. Since the buccal tablet

remains stationary at the buccal mucosa, it is in constant contact with the buccal mucosa.
Hence it is able to provide better bioavailability compared to the gum.
Also the compliance rate of the gum is less due to undesirable taste and gastrointestinal
adverse effects. The mucoadhesive buccal tablets showed better compliance in human
volunteers.
Advantages of the invention
1. The composition overcomes the severe break through cravings experienced as withrawal symptoms by heavy smokers.
2. The composition can be self administered. The therapy can be discontinued when desired. And hence can be manipulated to suit the users need.
3. The release of nicotine from the composition is rapid.
4. The composition is convenient and quantitative on the basis of the amount of substance (drug) to be delivered into systemic circulation through buccal mucosa.
5. The composition is user friendly.

We Claim
1. A mucoadhesive buccal composition useful for smoking cessation, which comprises
hydrophilic polymers, nicotine, starch, colloidal carriers and excipients, the excipients having
the property of controlling the release of nicotine, the resulting composition being provided
with a backing membrane to facilitate unidirectional release of nicotine.
2. The mucoadhesive buccal composition as claimed in claim 1 wherein nicotine is adsorbed
on colloidal carriers which has the property of adsorbing liquid before mixing with the
excipients.
3. The mucoadhesive buccal composition as claimed in claim 2 wherein the colloidal carriers
such as silica, or silicon dioxide (silicium dioxide), is used.
4. The mucoadhesive composition as claimed in claims 1 to 3 wherein hydrophilic polymers used are selected from a water insoluble, water-swellable cross-linked polycarboyllic polymer, and a water soluble polymer.
5. The mucoadhesive buccal composition as claimed in claim 4 wherein the polymer used is selected from hydroxypropylmethyl cellulose carbopol and other water swellable forms of cellulose, carbopol and other water-swellable forms of cellulose and polymers and the like.
6. The mucoahesive buccal composition as claimed in claims 1 to 5, wherein the ratio of the polymers used ranges from 5:10 to 5:30.
7. The mucoadhesive buccal composition as claimed in claims 1 to 6 wherein the concentration of the polymers used ranges from 10-40%.
8. The mucoadhesive buccal composition as claimed in claims 1 to 7 wherein the excipients used is selected from magnesium stearate, stearic acid and talc.
9. The mucoadhesive buccal composition as claimed in claims 1 to 8 wherein the backing membrane is selected from pressure sensitive acrylate adhesives.

10. The mucoadhesive buccal composition as claimed in claims 1 to 9 wherein the amount of nicotine used in the composition is 5mg.
11. A process for the preparation of mucoadhesive buccal composition useful for smoking cessation which comprises, adsorbing nicotine on colloidal carrier-silicon dioxide, mixing hydrophilic polymers, starch and excipients, the excipients having the property of controlling the release of nicotine, the resulting mixture compressed on a tablet compression machine and tablet formed being provided with a backing membrane to facilitate unidirectional release of nicotine.

12. The process as claimed in claim 11 wherein Nicotine is adsorbed on colloidal carriers
which has the property of adsorbing liquid before mixing with the excipients.
13. The process as claimed in claims 11 & 12 wherein the colloidal carriers such as silicon
dioxide are used.
14. The process as claimed in claims 11 to 13 wherein hydrophilic polymers used are selected
from a water insoluble, water swellable cross linked polycarboxylic polymer, and a water
soluble polymer.
15. The process as claimed in claim 14 wherein the polymer used is selected from HPMC or
hydroxypropylmethyl cellulose and other water swellable forms of cellulose and polymers and
the like.
16. The process as claimed in claims 11 to 15 wherein the excipients used are selected from magnesium stearate, stearic acid and talc.
17. The process as claimed in claims 11 to 16wherein the backing membrane is selected from polyisobutylene, acrylate adhesives or silicone adhesives.
18. The process as claimed in claims 11 to 17 wherein the amount of nicotine used in the
composition is 5mg.
19. The mucoadhesive buccal composition useful for smoking cessation substantially as herein described with reference to the Examples 1 to 9.
20. The process for the preparation of mucoadhesive buccal composition useful for smoking cessation substantially as herein described with reference to the examples 1 to 9.

Documents:

0968-che-2004 abstract-duplicate.pdf

0968-che-2004 claims-duplicate.pdf

0968-che-2004 description (complete)-duplicate.pdf

968-che-2004-abstract.pdf

968-che-2004-claims.pdf

968-che-2004-correspondnece-others.pdf

968-che-2004-correspondnece-po.pdf

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

968-che-2004-form 1.pdf

968-che-2004-form 19.pdf

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Patent Number

221428

Indian Patent Application Number

968/CHE/2004

PG Journal Number

37/2008

Publication Date

12-Sep-2008

Grant Date

23-Jun-2008

Date of Filing

23-Sep-2004

Name of Patentee

THE MANIPAL COLLEGE OF PHARMACEUTICAL SCIENCES

Applicant Address

MAHE, MAINPAL, MADHAV NAGAR, MAINPAL 576104

Inventors:

#	Inventor's Name	Inventor's Address
1	NAYANABHIRAMA UDUPA	MAHE, MAINPAL 576104
2	SHAILA LEWIS	MAHE, MANIPAL 576 104,

PCT International Classification Number

A61F13/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA