FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Provisional Specification
(See sectionl0 and rule 13)
TRANSMUCOSAL COMPOSITION
PANACEA BIOTEC LIMITED
A COMPANY INCORPORATED UNDER THE LAWS OF INDIA HAVING THEIR
OFFICE AT 104, SAMARPAN COMPLEX, NEW-LINK ROAD, CHAKALA, ANDHERI
(E), MUMBAI400099, MAHARASHTRA, INDIA

The following specification describes the invention

TECHNICAL FIELD
The present invention relates to a novel composition and method suitable for delivering
active agents through transmucosal administration. Transmucosal administration includes
administration of drug via, oral, nasal, rectal or vaginal mucosa.
The novel transmucosal composition of the present invention is such that it is easy to
manufacture and handle, provides more uniform & controllable serum concentration of the
active agent by avoiding the first-pass and degradation in the g.i.tract, is superior in handling
on application and is equally superior in (i) easy removal of the novel dosage form when its
application is no longer required and (ii) in safety.
The transmucosal composition of the present invention is more suitable for intraoral and/or
intranasal delivery, particularly suitable for delivering active agents through the sublingual
route and/or buccal tissue.
BACKGROUND OF THE INVENTION:
Transmucosal delivery through absorptive mucous membranes such as oral, buccal, sublingual, eye, nasal, pulmonary, rectal, and vaginal membranes, has the advantage of being noninvasive and of bypassing hepato/gastrointestinal clearance, but these mucous membranes, similarly to the skin, is lined by multiple layers of stratified, squamous epithelium cells, is complex and not readily permeable to any and all molecules desired to be delivered via the mucosal surface. Novel compositions and methods are still in need to be developed for delivering active agents especially the proteins, peptides, carbohydrates, macromolecules and complex agents and others that may require to be delivered by avoiding g.i. tract, such that the composition delivers the active agents readily, uniformly, with a predictable control over drug release and convenience of taking it off from the mucosal surface by the user on achieving the required therapeutic effect, which is most essential to

avoid excess systemic circulation of unwanted drug to avoid adverse effects. In order to take advantage of the above-mentioned patient convenience and compliance factor, even normal drugs, which are available for oral delivery, may be formulated as transmucosal compositions for suitable delivery through the mucosa.
The nasal cavity provides an attractive route for peptide and protein delivery because of its relatively high permeability and ease of administration (in comparison to the invasive injectable route). Conventional nasal sprays, drops, gels, patches and novel composition of the present invention are suitable dosage forms for delivering drugs through the nasal mucosa.
Transvaginal compositions for delivery of drugs to the uterus through the vaginal mucosa are being studied recently for treatment of dysmenorrhea, urinary tract infections and others. Contraceptives may also be suitable for delivery via vaginal mucosa.
Mucous membranes of the oral cavity are well preferred as sites for drug administration. The sublingual route, which includes the membrane of the ventral surface of the tongue and the floor of the mouth, is more permeable to drugs and gives faster absorption and higher bioavailabilities of many drugs. It is a well-known route for administration of nitroglycerin, buprenorphine and nifedipine. The buccal mucosa in the oral cavity, which constitutes the lining of the cheek and the lips, is equally convenient and easily accessible and is more suitable for delivery of drugs in the local buccal cavity and across the buccal mucosa into the systemic circulation both as immediate delivery systems and as controlled or retentive delivery systems. Both the buccal and sublingual membranes offer certain advantages over the other routes of administration. These include a fast onset of action, by-passing the first-pass effect of hepatic metabolism, ease of administration and avoidance of degradation in the gastric and intestinal fluids, more flexible and control over delivery of active agents.

Various dosage forms for buccal and other transmucosal delivery of active agents are well known in the art. These commonly include films, patches, tablets, sprays, lozenges, gums, and thereof.
The term "buccal patch" or "film" typically refers to a flexible film that adheres to the oral mucosa and delivers a drug over a period of time. These can be either quick dissolving or dispersing films, or can have mucoadhesive properties with drug released over a period of time. These films or patches are typically prepared by mixing the active ingredients with suitable polymers and other excipients, heating the mix, pouring or extruding to form sheets, which are then dried under controlled humidity and temperature conditions to drive off excess moisture. The finished sheets of films are cut into strips, which are then sized to deliver the exact amounts of medications. The disadvantage of these methods is the relatively long time period required for drying the films, requirement to maintain tight control over the drying conditions, and the relatively high moisture content of the finished dosage form. Also, the heating step required may preclude the incorporation of heat-sensitive active agents. Another option for a buccal dosage form is to prepare a buccal spray containing the actives along with solvents and optionally propellants. These sprays produce a fine mist of the active, which deposits onto the buccal mucosa, from where they are absorbed. The disadvantages of these types of dosage forms are the need for solvents, propellants that can be toxic, expensive and require special precautions during manufacture. Also, it is difficult to formulate prolonged release compositions by this method.
Lozenges and gums release the drug as the dosage form is sucked, or chewed. In addition to buccal absorption, most of the drug released flows with the saliva into the gastric cavity. The release shows variability depending on how fast it is chewed or sucked. Buccal tablets are relatively convenient to manufacture and formulate. Matrix type tablets are prepared by dispersing the active agents in suitable bioadhesive polymers, and other

excipients. Many employ the use of penetration enhancers for optimal penetration of the active agent through the mucosa. However, interactions between the active agents and the adhesives modify the drug release pattern, and may also cause instability of the system. One solution to this problem is the preparation of multilayered tablets, which segregate the interacting ingredients. However, multilayered tablets are often prone to the problem of separation of layers. Also, since only the adhesive layer is attached to the mucosa, the active agent in the opposing layer has to first enter this layer, and migrate through it to be available for absorption. Alternatively, the tablet has to be placed in the gingival cavity between the mucosa of the lips and the gum, so that the adhesive layer sticks to the gums and the drug is absorbed through the mucosa of the lips. Thus, this type of dosage form faces many restrictions on the location in the mouth where they can be placed.
All these above-mentioned limitations in the various dosage forms for buccal delivery of active agents has resulted in very few products that are viable commercially. Thus, there is a need for an improved dosage form for buccal administration of active agents which is simple, easy to manufacture, convenient to administer, provides good stability, flexible to allow wide variations in delivery pattern, and importantly, user-friendly.
It is an object of the present invention to provide a novel dosage form for delivery of active agents through the oral mucosa, such that it is easy to manufacture and handle, exhibits good stability and provides flexibility and predictable control over drug release. The novel dosage form of the present invention is such that it promotes high patient acceptance and compliance.
It is thus an object of the present invention, to provide a novel composition suitable for delivering active agents through the transmucosal administration via the nasal, vaginal or more suitably through the intraoral mucosa. The novel composition suitable for buccal delivery of active agents is such that it is easy to apply at the site of action and equally easy to

remove when unnecessary, additionally it is also adapted to provide the user with a control over the amount of active agent that is absorbed and hence adjust the therapeutic effect as desired. When not essential or when the therapeutic effect has been achieved the user has the flexibility to remove the dosage form easily and thus avoid the unnecessary side-effects which is the major concern for most of all the active agents used for treatment of any disease. Most of the intraoral dosage forms, especially the dosage forms to be placed in the buccal cavity regions, face the problem of being such that they either get detached from the site of adhesion before the drug is delivered due to inappropriate adhesion or they adhere so strongly that it leads to causing of abrasion and peeling-off of the epithelial region while trying to remove the system from the place.
The novel composition for transmucosal administration of the present invention is a novel transmucosal disk that can be prepared by the simple and commercially feasible technique of compression. The composition of the invention is a novel compressed transmucosal disk for intraoral delivery, especially buccal delivery of active agents, comprising of the active agent, mucoadhesive substances and carriers thereof. The composition is such that it has two compartments and the active agent and the mucoadhesive substances are included in substantially segregated compartments. Further, the composition is a novel compressed transmucosal disk wherein; both the active compartment and the mucoadhesive compartment are in contact with the same mucosal surface. Preferably, the dosage form is a novel compressed transmucosal disk, which is prepared by multiple-compression steps. More preferably, the novel compressed transmucosal disk has the mucoadhesive compartment on three sides of the inner active compartment, such that when placed in the oral cavity two ends of the mucoadhesive compartment is attached to the mucosal surface on wetting, facilitating direct contact of the inner compartment with the mucosal surface, backed by the third side of the mucoadhesive compartment. The active agent is preferably contained in the inner

compartment. This would also ensure that the active agent is unidirectionally absorbed directly through the mucosal membrane and is prevented from getting swallowed with saliva and transferred into the gastrointestinal tract. This along with the ability of easy removal of the disk when not desired provide for better control of the serum concentration of the active agent and better patient compliance.
DESCRIPTION OF THE INVENTION
The novel compressed transmucosal disk of the present invention is comprised of an inner compartment and an outer compartment. The inner compartment is surrounded on three sides by the outer compartment, such that only one surface of the inner compartment is exposed. Dosage forms of such type are known in the art by various names such as "inlay tablets", "bull's-eye tablets" or "dot tablets". Preferably the inner compartment contains the active agent or agents in combination with suitable excipients and the outer compartment contains the mucoadhesive polymers. Optionally active agent may be present in both the inner and outer compartment.
The advantage of this system is that the tablet can be placed in the body cavity such that the exposed surface of the active compartment is in direct contact with the mucosal surface, along with the two ends (the one above and the one below the inner compartment) of the surrounding "ring" of the mucoadhesive compartment which adheres to the mucosal surface ensuring proper holding of the inner compartment and direct absorption of the active agent from the inner compartment. The surrounding "ring" of the mucoadhesive compartment adheres the system in place. In case of buccal delivery, the advantage is that such a system can be placed virtually anywhere in the buccal cavity, either in the gingival compartment or on either of the cheek mucosa. The inner and the outer compartment may be of different color to distinguish the compartments for purpose of application and facilitates proper application

of the system by the user, wherein the inner compartment is directly adhered to the buccal mucosal. Also, due to segregation of active agents and the mucoadhesive polymers, their interaction is minimized.
Release of the active agent can be immediate or prolonged, depending upon the composition of the active compartment. Thus the system provides wide flexibility for the pattern of drug delivery. The preferred composition is such that when placed in the desired mucosa, the drug delivery is initiated and continues for a period of time sufficient to provide the beneficial effect, after which it can be removed whenever required.
The other advantages of the present invention are that it reduces the chances of dose dumping, unnecessary burst effects and failure of the system, which are otherwise usually associated with simple matrix or reservoir systems.
One main feature of the invention is that the transmucosal disk is easily peelable, since only a ring of mucoadhesive compartment holds it in place. In certain conditions like pain, migraine, nocturia, and others where a user can decide the level of therapeutic efficacy required, the system is adapted to be removed when the desired effect has been achieved. This can also be beneficial considering that people differ from region to region and hence the level of active agents required to produce a therapeutic end-point also differ. In such cases, doses can be easily titratedi on an individual basis, so that once the desired relief is achieved, the disk can simply be peeled off, and the occurrence of side effects can be minimized. Thus the novel composition of the invention is suitable as pealable transmucosal disk suitable for taking care of variable drug requirement
Additionally, the system can be designed such that after the drug delivery is complete, the mucoadhesive compartment will dissolve or disintegrate away, requiring no additional disposal.

The method of preparation of these tablets, which may be made of suitable thickness, may be also as thin wafers, as suitable and required for delivery of actives, is similar to the preparation of compression- coated tablets except that a surface of coating is eliminated. The dosage forms of the invention are manufactured by techniques well known in the art. For the core compartment, the active agent is compressed together with other suitable excipients. The contents of the mucoadhesive compartment are blended uniformly to form a premix. The core is then incorporated into this premix, preferably by a transfer and centering mechanism of the compression machine, such that the premix surrounds the core on three sides in the die cavity. This assembly is then compressed to form the "inlay system". The system is made sufficiently thin to promote patient compliance and mouth-feel.
The actives suitable for incorporation in this system are any drugs, which would show beneficial effects on mucosal absorption. Such drugs include those that require a fast onset of action, extended effects, are degraded in the gastric or intestinal juices, undergo pre-systemic clearance etc. In general these include, but are not limited to antiinfectivesi such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; antihelminthics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; Antidiabetic agents; antidiarrheals; antihistamines; antiinflammatory agents; antimigraine preparations; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including potassium and calcium channel blockers, beta-blockers, alpha-blockers, and antiarrhythmics; antihypertensives; diuretics and antidiuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; vasoconstrictors; cough and cold preparations, including decongestants; hormones such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressives; muscle relaxants; parasympatholytics; psychostimulants; sedatives; and

tranquilizers. By the method of the present invention, both ionized and nonionized drugs may be delivered, as can drugs of either high or low molecular weight.
Of special relevance to the invention are active agents, which are proteins, peptides, carbohydrates and other agents which exhibit extensive first pass metabolism. Proteins, peptides, carbohydrates are generally absorbed to a very less extent form the gastrointestinal tract, due to local degradation and first pass effect. Hence they are often given by parenteral routes, such as intravenously or subcutaneously. However, these routes have many disadvantages. Hence, the novel transmucosal composition of the invention would be particularly advantageous for such drugs. Examples of proteins and peptides that can be utilized include, but are not limited to oxytocin, vasopressin, adrenocorticotrophic hormone, epidermal growth factor, prolactin, luliberin or luteinising hormone releasing hormone, growth hormone, growth hormone releasing factor, insulin, somatostatin, glucagon, interferon, gastrin, tetragastrin, pentagastrin, urogastroine, secretin, calcitonin, enkephalins, endorphins, angiotensins, renin, bradykinin, bacitracins, polymixins, colistins, tyrocidin, gramicidines, and synthetic analogues, modifications and pharmacologically active fragments thereof, monoclonal antibodies, antigens and soluble vaccines.
Examples of other drugs that undergo extensive first pass metabolism include, but are not limited to agents like isosorbide mononitrate, isosorbide dinitrate, nifedipine, nitroglycerin, propranolol, lignocaine and others thereof.
The active compartment may also include absorption-promoting agents, also known as permeation enhancers, which increase the flux of the permeants across the mucosa. The absorption-promoting agents is selected from the group consisting of cell envelope disordering compounds, solvents, steroidal detergents, bile salts, chelators, surfactants, non-surfactants, fatty acids, and any other chemical enhancement agents and the likes thereof.

The active compartment may also optionally include other excipients, like diluents, fillers, binders, lubricants, glidants, flavoring agents, sweetening agents, coloring agents, stabilizers, enzyme inhibitors, lubricants and optionally various rate-controlling polymers. The system can be designed for immediate, delayed, sustained, controlled, extended, pulsed or any other type of release of the active agent. Techniques for doing this are well known in the art. The release can take place by diffusion, erosion, facilitated by direct solubilization of the active in contact with the mucosal surface, or dissolution or dispersion in the fluid, which diffuses across the mucoadhesive layer.
The outer mucoadhesive compartment contains adhesive agents, in addition to other suitable excipients. Oral adhesives are well known in the art. Typically, these adhesives consist of a matrix of a hydrophilic, e.g., water soluble or swellable polymer or mixture of polymers that can adhere to a wet mucous surface. They generally belong to the category of celluloses, carbomers, natural gums, vinyl derivatives and combinations thereof. Examples include, but are not limited to, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, ethylcellulose, carboxymethyl cellulose, dextran, guar-gum, polyvinyl pyrrolidone, polyvinyl acetate, pectins, starches, gelatin, casein, acrylic acid polymers, polymers of acrylic acid esters, acrylic acid copolymers, vinyl polymers, vinyl copolymers, polymers of vinyl alcohols, carboxy vinyl polymers and copolymers, vinyl esters, alkoxy polymers, polyethylene oxide polymers, polyethers, and mixtures thereof. In addition, the compartment can also contain other excipients for ease of manufacturing, handling, patient compliance and functionality of the dosage form.
The following non-limiting examples illustrate an embodiment of the invention and should not be construed to limit the scope of the invention.

Example 1

No. Ingredient mg/tab
Active Compartment
1 Desmopressin acetate 0.1
2 Lactose monohydrate 49.4
3 Magnesium stearate 0.5
Mucoadhesive Compartment
1 Carbopol 974P 40
2 Microcrystalline cellulose 98.6
3 Magnesium stearate 1.4
Active Compartment: Blend the excipients with the active agent desmopressin. Lubricate it further with magnesium stearate in a suitable blender. Compress the blend using a suitable punch on a rotary tablet compression machine.
Mucoadhesive Compartment: Blend the contents given in this compartment to get a uniform mixture of the excipients and the mucoadhesive polymer. Incorporate the compressed active compartment described above into this blend and compress on a rotary tablet compression machine.
Example 2

No. Ingredient mg/tab
Active Compartment
1 Desmopressin acetate 0.1
2 Lactose monohydrate 15.6

3 Hydroxypropyl methylcellulose 15.0
4 Magnesium stearate 0.5
Mucoadhesive Compartment
1 Polyvinyl acetate 40
2 Microcrystalline cellulose 98.6
3 Magnesium stearate 1.4
Manufacturing procedure is same as described in example 1 above.

Dated this May 2nd of 2006

FOR PANACEA BIOTEC LIMITED (Dr. MAHALAXMI ANDHERIA)

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