Title of Invention

A SYSTEM FOR SPATIALLY AND TEMPORALLY PROGRAMMABLE DELIVERY OF AN ACTIVE AGENT

Abstract The present invention is concerned with a system for spatially and temporally programmable delivery of an active agent. When administered orally, the system can be retained in the gastric region for a prolonged period of time. It comprises of a core, one or more layers coated over the core and a performed hollow space. The invention also concerns with a process for preparation of the system and a method for treating/preventing diseases, by administering to a subject in need thereof, the system of the invention.
Full Text FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Provisional Specification
{See section 10 and rule 13)
BUOYANT PROGRAMMABLE DELIVERY TECHNOLOGY
PANACEA BIOTEC LIMITED
A COMPANY INCORPORATED UNDER THE LAWS OF INDIA HAVING THEIR
OFFICE AT 104, SAMARPAN COMPLEX, NEW-LINK ROAD, CHAKALA, ANDHERI
(E), MUMBAI 400099, MAHARASHTRA, INDIA
The following specification describes the invention
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FIELD OF THE INVENTION
The invention is in the field of pharmaceutical science. It relates to a therapeutic system which is retained in the stomach for a prolonged period of time. The system can be programmed to provide any desired type of drug release profile.
BACKGROUND OF THE INVENTION
Gastric retention systems for delivery of drugs in the upper part of the gastrointestinal tract are well known. Some drugs show preferential solubility and/or absorption in the stomach or the proximal part of the gastrointestinal tract. In such cases, gastric retention systems can deliver drugs at their preferred site of absorption, thereby improving bioavailability and reducing drug wastage. Such systems also find applications for delivery of drugs which act locally in the gastric and proximal intestinal regions, such as antacids, anti-ulcer agents etc. Other applications include delivery of drugs which exhibit a narrow absorption window, drugs which degrade in the colon and drugs that are poorly soluble at an alkaline pH.
Various approaches have been used to formulate systems which exhibit a prolonged gastric residence. These approaches include utilization of mechanisms such as bioadhesion, swelling, floatation, sedimentation, rafts and unfolding systems and simultaneous administration of gastro active agents.
An approach for increasing the gastric residence time is to produce floating systems. These systems have a density less than the gastric fluids and hence they tend to float in the stomach. Since the pylorus i.e. the exit to the intestines, is located in the lower part of the stomach, they are not discharged into the intestines for a long period of time.
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One mechanism to produce floatation is to produce effervescent systems. (Dave et al, Gastroretentive Drug Delivery System of Ranitidine Hydrochloride: Formulation and In Vitro Evaluation, AAPS PharmSciTech, 5, 2, Article 34, 2004; Ichikawa M, et al, A new multiple unit oral floating dosage system. I: Preparation and in vitro evaluation of floating and sustained-release kinetics, J Pharm Sci, 80, 1991; Ozdemir Net al, Studies of floating dosage forms of furosemide: in vitro and in vivo evaluation of bilayer tablet formulation, Drug Dev Ind Pharm. 26, 2000). These systems utilize gas-generating materials, such as carbonates. On reacting with the gastric acids, the materials generate carbon dioxide, which inflates the system and allows it to float. Such systems are however highly dependant on gastric conditions, such as acidity, for successful functioning. An approach to make them independent of gastric acids is to incorporate pharmaceutically acceptable acidic substances, along with basic substances into the formulations, and then allowing them to react when the system comes in contact with a fluid, such as the gastric fluid. These systems, however, generally become moisture sensitive and present mechanical and chemical stability problems, making their manufacturing and packaging cumbersome.
Another approach is to incorporate buoyant materials into the system, which causes it to float. Hydrophobic materials, such as lipids, oils and waxes are used for these purposes. (Sriamornsak P. et al, Morphology and Buoyancy of Oil-entrapped Calcium Pectinate Gel Beads, The AAPS Journal, 6, 3, 2004; Shimpi S, et al, Preparation and evaluation of diltiazem hydrochloride-Gelucire 43/01 floating granules prepared by melt granulation, AAPS PharmSciTech. 5, E43, 2004). Such materials often adversely affect the mechanical strength of the systems, present difficulty during manufacturing such as during compression, or utilize elaborate processes.
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Matrix type and bilayer systems are known which utilize swellable materials such as polymers, hydrocolloids etc. (US Patent No. 5232704 Sustained Release, Bilayer Buoyant Dosage Form) The swellable materials, such as alginate, polymers, gums swell on-coming in contact with fluids, reduce the density of the system and causes it to float. The increase in size of the system may also present a mechanical barrier preventing exit through the pylorus. However, in practical use, these systems often exhibit inadequate performance, reproducibility issues or need elaborate processing requirements. Also, the functional materials used in these systems are often not biodegradable. As a result, a ghost of the system remains, which may pass through the intestines unchanged and cause unacceptable blockages.
All of these above mechanisms require the presence of fluids to activate their floatation characteristics. They tend to be dependant on gastric conditions to function effectively. But gastrointestinal conditions are inherently highly variable. The conditions depend upon and vary with many physiological factors such as diet, fluid intake, age, gender, stress conditions and disease states. Hence, although successful in in-vitro conditions, many such systems fail to function effectively in the human physiology.
To overcome some of the above mentioned problems, dosage forms such as hollow or light microcapsules and beads have been formulated. (Talukder R et al, Gastroretentive Delivery Systems: Hollow Beads, Drug Development and Industrial Pharmacy, 30, 4, 2004; Streubel A et al, Floating microparticles based on low density foam powder, Int J Pharm, 241, 2002; Unites States Patent No. 6207197 Gastroretentive controlled release microspheres for improved drug delivery). Although these systems are less dependant on gastric conditions,
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they often utilize specialized and costly raw materials and involve elaborate complex, variable and time consuming processes, which are expensive and not very scale-up friendly.
Aerogels and foam materials have been used to produce floating systems. Due to entrapped air and gases in their hollow spaces, they are inherently less dense and hence float on the gastric fluids. Unites States Patent No. 5626876 discloses floatable oral therapeutic systems which use microporous materials having a high void proportion for obtaining low specific gravity. The materials used are thermoplastic polymers, natural polymers and inorganic compounds such as glasses and ceramic materials. The invention relates to preparation of microporous materials by processes such as granulation, hot melting, compression or molding. Unites States Patent No. 3976764 discloses solid therapeutic preparations floatable in the gastric juice wherein the active ingredient is impregnated into a body of empty globular shell or a small granular lump of a material having high buoyancy. The empty shells of the invention are gelatin capsules coated with active ingredients. The invention also discloses pop-corn or pop-rice type of materials coated with active ingredients.
Using microporous materials tends to increase the bulk of the systems. There is also less flexibility for designing the dosage form and incorporating active ingredients. Including actives within the pores decreases the functionality and coating the actives over the porous materials increases the size and limits the amount that can be incorporated into the system. Such systems may also be complex and less reproducible.
There is a need in the art to formulate a system which overcomes most of the above mentioned disadvantages, and is yet simple, safe, easy to manufacture and is functionally
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reproducible. Especially, there is a need for a system which does not depend on gastric conditions for it proper functioning.
It is an object of this invention to provide a gastric retention system which meets most of the above mentioned needs.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to a therapeutic system for prolonged gastric retention which
can be used for delivery of drugs which benefit from inclusion in such a system.
The present invention relates to a therapeutic system for prolonged gastric retention which is substantially independent of gastric conditions for it proper functioning.
The present invention relates to a therapeutic system for prolonged gastric retention which can be adapted to provide any desired type of drug release profile.
The present invention relates to a therapeutic system for prolonged gastric retention which floats on the gastric fluid to prolong its gastric residence time.
The present invention relates to a therapeutic system for prolonged gastric retention which does not require the presence of gastric fluids to activate its floatation mechanism.
By 'drug' as used herein is meant an agent, active ingredient, substance or compound having beneficial physiologic, prophylactic and/or therapeutic properties when administered to an animal, especially humans. The term 'drug' also includes solvates, hydrates, active
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metabolites, prodrugs, derivatives, and all pharmaceutically acceptable complexes and salts thereof.
By 'modified release' as used herein is meant release, which is not immediate release and is taken to encompass controlled release, sustained release, prolonged release, timed release, retarded release, extended release, pulsatile release and delayed release.
The present invention provides a therapeutic system for prolonged gastric retention, which is a coated system, comprising a core and coated with a plurality of layers. The system may be in any form, such as tablets, caplets, multiparticulate systems such as granules, pellets and beads or miniaturized system such as minitablets.
The system of the invention comprises of the following chief layers:
1. the innermost core compartment,
2. an optional first polymeric layer,
3. a second polymeric layer,
4. drug containing layer.
In addition to the being present in the drug containing layer, drug candidates can optionally also be incorporated into the other layers.
The manufacturing of the therapeutic system of the invention is done using processes and equipments commonly used in the manufacture of solid dosage forms. The core of the system is manufactured by blending the appropriate ingredients, optionally including a drug, preparing granules by wet granulation or dry granulation followed by compression of the granules. Alternatively, the core is manufactured by direct compression or by molding. All
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these processes, including their various modifications, are well known to a person skilled in the art. In case of multiparticulate systems, the cores may be manufactured as small pellets, or pre-formed materials, such as non-pareil seeds or pellets prepared by extrusion spheronization technique, may be used. To incorporate drugs in pre-formed cores, the cores are coated with the drug layer.
In an embodiment, the core thus formed is coated with the first polymeric layer. The layer may contain hydrophilic or hydrophobic materials. Solvents utilized for coating may be aqueous, organic or mixtures thereof.
In an alternate embodiment, the first polymeric layer is absent, and the above mentioned materials are incorporated within the core compartment. The core compartment may then be manufactured to contain high percentages of moisture and/or solvents. The core is also manufactured such that its surface has low adherence to the overlying polymeric layer.
The subsequent layer coated is the second polymeric layer which contains polymers substantially insoluble in the gastric fluids. Heat applied at this stage, in the range of 40°C to 150°C, depending on the solvents and polymers used, causes the moisture and/or solvents in the first polymeric layer or the core compartment to evaporate, generating enough vapor pressure to exert force on the inner walls of the second polymeric layer. Due to the presence of plasticizers in the second polymeric layer, it has a lower glass transition temperature and a decreased modulus of elasticity. This causes the second polymeric layer to expand, leading to the generation of a hollow space. On cooling, or by additionally applying vacuum, at a stage that the second polymeric layer neither collapses, nor cracks, the polymeric layer hardens to provide a hollow space with good structural integrity and reproducibility. The space may
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contain air, water-vapour, solvent vapour, any gas, a mixture of gases or a partial vacuum. The space may be continuous or discontinuous i.e, the layers of the system inside the hollow space may stick to the layers outside the hollow space at single or multiple points.
After hardening of the second polymeric layer, it is then coated with the drug containing layer. A solution or suspension of the drug, along with suitable excipients, is sprayed over the system. The drug layer is formulated and manufactured as per the drug or drugs included and the release profiles desired. The drug layer may be further coated with a functional or nonfunctional layer as per the desired purpose.
An optional layer may also be coated between the second polymeric layer and the drug containing layer, to separate and isolate the ingredients of the two layers. Any such and other modifications which would be obvious to a person skilled in the art based upon the disclosure herein, and which fall within the spirit and scope of the invention, are also considered to be included within the invention.
This process may be carried out utilizing commonly used equipments such as pan coaters, fluid bed processors, rotary evaporators, vacuum driers or freeze driers. A person skilled in the art is well versed with the working and functioning of such equipments and can easily obtain the desired results.
The therapeutic system of the invention thus obtained has a hollow space, generated in-situ, during the manufacturing process. This imparts a low density to the system, such that on ingestion, the system, due to its buoyancy, floats on the gastric fluid. By varying the formulation characteristics, the system can be programmed to have any desired gastric
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retention time period. During this period, the drug in the drug containing layer is released in the gastric or proximal areas of the gastrointestinal tract. The second polymeric layer made of gastric insoluble polymers does not dissolve in the gastric conditions and maintains the integrity of the system. As the system reaches the lower part of the gastrointestinal tract and as the pH increases, the second polymeric layer starts to erode or dissolve, exposing the inner optional polymeric layer and/or the core to the gastrointestinal environment. The drug or drugs contained in the innermost core compartment are then released as per the desired release profile. Optionally the core may not contain any drug.
A detailed description of the layers of the general embodiment of the system is given in details as follows:
Core or Core compartment:
The innermost area of the system is the core. The core may be a compressed or molded system as in case of solid unit dosage forms or can be non-pareil seeds, pre-formed pellets or compressed systems as in case of multiparticulate dosage forms. The core comprises of any excipients normally encountered in the art such as fillers, diluents, binders, disintegrants, glidants, lubricants etc. A few exemplary substances include lactose, starch, starch derivatives, celluloses, inorganic salts such as dibasic calcium phosphate, polysaccharides, stearic acid and its salts/esters, functional and non-functional polymers etc. A complete list of such excipients described in detail can be found in the Handbook of Pharmaceutical Excipients, 3rd Edition, A. H. Kibbe, Editor, American Pharmaceutical Association, and Pharmaceutical Press (2000).
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The core can optionally comprise of one or more drugs. It is formulated to release the drug either all at once or in a modified release fashion. Methods to obtain such release profiles are well known in the art. For modified release, use is made of rate controlling polymers or any other excipients known for such purpose. Rate controlling excipients include, for example, various natural and synthetic polymers, gums of plant, animal, mineral or synthetic origin, substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes. The drug is incorporated into a matrix of such substances and then released by erosion of or diffusion through these matrices.
In case of drugs which exhibit low bioavailability, such as proteins, peptides and other macromolecules, absorption enhancers may be included in the core. These enhancers assist in increasing the absorption of drug molecules through the gastrointestinal mucosa and improving their bioavailability. Absorption enhancers which may be used belong to categories such as cell envelope disordering compounds, solvents, steroidal detergents, bile salts, chelators, surfactants, non-surfactants, fatty acids etc.
The core, in certain embodiments, may also contain hydrophilic or hydrophobic materials and a percentage of moisture and/or solvents sufficient for generation of adequate vapor pressure to form a hollow space, during the heating stage.
Optional first polymeric layer:
Adjacent to the core may be the optional First polymeric layer. It comprises of one or more hydrophilic or hydrophobic materials.
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Non-limiting examples of such materials may be hydrophilic or hydrophobic polymers, such
as alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkyl alkylcelluloses,
carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters; other natural, semisynthetic, or synthetic polysaccharides, such as, alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gum arabicum, guar gum, xanthan gum, starches, pectins, such as sodium carboxymethylamylopectin, chitin derivates, polyfructans, inulin; polyacrylic acids and the salts thereof, polymethacrylic acids and the salts thereof, methacrylate copolymers; polyvinyl alcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide; natural and synthetic fats, lipids and waxes, substituted or unsubstituted hydrocarbons etc.
The first polymeric layer may also include hygroscopic or deliquescent materials such as polyethylene glycol, propylene glycol, polypropylene glycol, sodium chloride and other inorganic salts, or any suitable other materials.
The layer also includes auxiliary agents useful in coating compositions such as plasticizers, pigments, surfactants, fillers, pore-forming agents, anti-foam, anti-tacking agents etc.
Second polymeric layer:
The second polymeric layer is coated over the core or the optional first polymeric layer and substantially encapsulates it. It comprises chiefly of polymers which are insoluble or less
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soluble in the gastric fluid. The solubility of such polymers may be pH-dependant or pH-independent.
Examples of pH-dependent polymers include enteric cellulose derivatives, enteric acrylic acid-based copolymers, enteric maleic acid-based copolymers, enteric polyvinyl derivatives, etc.
Specific examples of enteric cellulose derivatives include, but are not limited to,
hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate,
hydroxymethylethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate
succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate
phthalate, methylcellulose phthalate, carboxymethylethylcellulose,
ethylhydroxyethylcellulose phthalate, etc.
Specific examples of enteric acrylic acid-based copolymers include, but are not limited to, styrene-acrylic acid copolymers, methyl acrylate-acrylic acid copolymers, methyl acrylate-methacrylic acid copolymers, butyl acrylate- styrene-acrylic acid copolymers, methacrylic acid-methyl methacrylate copolymers (for example, product name: Eudragit LI00, Eudragit S, etc.), methacrylic acid-ethyl acrylate copolymers (for example, product name: Eudragit L100-55, etc.) methyl acrylate-methacrylic acid-octyl acrylate copolymers, etc.
Specific examples of enteric maleic acid-based copolymers include, but are not limited to, vinyl acetate-maleic anhydride copolymers, styrene-maleic anhydride copolymers, styrene-maleic monoester copolymers, vinyl methyl ether-maleic anhydride copolymers, ethylene-maleic anhydride copolymers, vinyl butyl ether- maleic anhydride copolymers, acrylonitrile-
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methyl acrylate-maleic anhydride copolymers, butyl acrylate-styrene-maleic anhydride copolymers, etc.
Specific examples of enteric polyvinyl derivatives include, but are not limited to, polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate, polyvinyl acetoacetal phthalate, etc.
Non-limiting examples of pH independent gastric insoluble polymers include ethylcellulose, and semi-permeable polymers such as cellulose acetate and similar polymers.
The above-mentioned pH-dependant or pH-independent polymers may be used singly or in a combination of two or more.
The layer also includes auxiliary agents useful in coating compositions such as plasticizers, pigments, surfactants, fillers, pore-forming agents, anti-foam, anti-tacking agents etc. Alternatively, this layer may also include one or more drug candidate.
Drug containing layer:
The drug containing layer is coated over the second polymeric layer. This layer is applied by spraying a solution or suspension of the drug over the system. The solvents used for the purpose include aqueous solvents, organic solvents or their mixtures. One or more drug candidates included in this system are applied as a single layer. Alternatively, this layer is built up by multiple layering where different drugs are applied as different layers or layers with different excipients are alternated with each other.
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The drug containing layer may contain mucoadhesive substances which may further assist in retention of tablets in the gastric region, especially when the fluid levels in the stomach are low. Non-limiting examples of mucoadhesives which may be included are carbopol (various grades), sodium carboxy methylcellulose, methyl cellulose, polycarbophil (NOVEON AA-1), hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate, sodium hyaluronate, xanthan gum, fenugreek gum, locust bean gum, Kollidon VA 64 and combinations thereof.
The drug containing layer can be adapted to provide any type of desired drug release profile, such as an immediate release or a modified release. The release profile of the drug is controlled by formulating the layer as a matrix type system, wherein the drug is incorporated into a matrix of rate controlling materials. Alternatively, the layer is coated with a functional layer, using rate controlling materials, which modifies the drug release profile. Rate controlling excipients include, for example, various natural and synthetic polymers, gums of plant, animal, mineral or synthetic origin, substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes.
Optionally, the drug containing layer is further coated with a non-functional layer. Such a layer serves the purpose of improving handling characteristics, providing better physical and chemical stability, barrier properties, aesthetic appeal etc.
Optionally, this layer may include mucoadhesive polymers.
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Drugs:
The drugs encompassed by the invention include any active ingredients which benefit from incorporation into such a system. Examples of such drugs include, but are not limited to, drugs used for alzheimer's disease, anaesthetics, acromegaly agents, steroidal and nonsteroidal anti-inflammatory agents, analgesics, antiasthmatics, anticancer agents, anticoagulants and antithrombotic agents, anticonvulsants, antidiabetics antiemetics, alcohol abuse preparations antiglaucoma, antiallergics, antihistamines, anti-infective agents, antiparkinsons, antiplatelet agents, antirheumatic agents, anti spasmodics and anticholinergic agents, antitussives, carbonic anhydrase inhibitors, cardiovascular agents, cholinesterase inhibitors, treatment of CNS disorders, CNS stimulants, contraceptives, cystic fibrosis management, dopamine receptor agonists, endometriosis management, erectile dysfunction therapy, urinary tract disinfectants fertility agents, gastrointestinal agents, immunomodulators and immunosuppressives, vitamins, nutritives, memory enhancers, migraine preparations, muscle relaxants, nucleoside analogues, osteoporosis management, drugs for respiratory organs, parasympathomimetics, prostaglandins, psychotherapeutic agents, sedatives, hypnotics and tranquillizers, macromolecules such as proteins, polypeptides, polysaccharides, vaccines, antigens, antibodies, drugs used for skin ailments, steroids and hormones, diagnostic agents; and combinations thereof.
Drugs incorporated into the drug containing layer are those that benefit from preferential delivery into the gastric and proximal intestinal regions. Such drugs include those having enhanced solubility in the gastric pH, drugs which are preferentially absorbed through the proximal regions of the gastrointestinal tract, drugs having an absorption window in the proximal regions of the gastrointestinal tract, drugs having stomach and proximal intestine as the local site of action and drugs degraded due to intestinal pH and/or enzymes.
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Drugs incorporated into the core compartment are those that benefit from preferential delivery into the distal regions of the gastrointestinal tract. Such drugs include those degraded in the acidic pH of the stomach, drugs having absorption window in the distal regions of the gastrointestinal tract, for drugs acting locally in the later part of the intestines and for colon delivery of drugs which undergo extensive Cytochrome P450 metabolic degradation in small intestine, especially for drugs that are substrates for CYP 3A4 isozymes which are predominant in the small intestine region.
Proteins, peptides, macromolecular drugs may also be delivered by incorporation into the core compartments such that they are targeted for release in the colon. In such cases absorption enhancers can also be included in the system to increase the bioavailability of such molecules.
The therapeutic system of the invention encompasses delivery of all types of drugs. They may be water soluble or insoluble, high dose or low dose. A complete list of drugs which can be included in the therapeutic system of the invention may be obtained from the Merck Index., 12th ed., 1996.
The size and shape of a gastric retention system can affect its gastric residence time. The therapeutic system of the invention can be tailored to a suitable size and shape as per the characteristics desired. The shape of the system may be round, caplet shaped or of any geometrical or odd shape. Multiparticulate systems may be filled into capsules for release into the gastric cavity, or compressed or molded into unit dosage forms. The size of the system is also an important formulation parameter. Generally, medium sized systems, such as
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with a diameter of around 7 to 8mm are found to show a better gastric residence as compared to larger tablets. The therapeutic system of the invention can be suitably sized.
The therapeutic system of the invention can be programmed to provide any desired type of drug release profile. The system can be programmed to provide both spatial and temporal controlled drug release.
According to an embodiment of the invention, the system is formulated such that the core is a placebo i.e. contains no drug. The system delivers the drug from the drug containing layer to the gastric and proximal intestinal regions.
In an embodiment, the drug release from the above mentioned system is substantially immediate.
In another embodiment the drug release from the above mentioned system is modified release.
As a further embodiment, the modified release from the above mentioned system is controlled by diffusion through or erosion of a matrix.
As an alternate embodiment, the modified release from the above mentioned system is controlled by application of a functional coating.
According to an embodiment of the invention, the system is formulated to contain a drug in the core compartment in addition to the drug containing layer. Such a system delivers the
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drug from the drug containing layer to the gastric and proximal intestinal regions and the drug in the core compartment to the later regions of the gastrointestinal tract.
In an embodiment, the drug release from the core compartment is substantially immediate.
In another embodiment the drug release from the above core compartment is modified release.
In an embodiment, drugs in both the compartments are released in a pulsatile manner, one immediately and the other after a predetermined delay.
In a further embodiment, one of the pulses is a modified release pulse.
In an alternate embodiment; both the pulses are modified release pulses.
According to an embodiment of the invention, the same drug is included both in the core compartment and the drug containing layer.
According to an embodiment of the invention, the system contains no drug containing layer and the drug is incorporated in the core compartment. Such a system may be useful for the delayed delivery of drugs to intestinal and colonic areas, since a prolonged delay may be achievable due to the floatation of the system in the gastric cavity.
As is clear from the above description, the therapeutic system of the invention demonstrates following advantages:
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The therapeutic system of the invention has a preformed hollow space. It does not require the gastric fluid to activate its floatation mechanism. Thus it is substantially independent of the gastric conditions for its proper functioning.
The therapeutic system of the invention is sophisticated, yet simple, functionally reproducible and upscalable.
The therapeutic system of the invention is easy to manufacture, amenable to large scale production, does not require sophisticated equipments and uses common raw materials which are biodegradable, non-toxic and biocompatible.
The therapeutic system of the invention is flexible with regards to formulation and can be spatially and temporally programmed to exhibit any type of desired drug release profile.
The therapeutic system of the invention provides delivery of two different drug candidates having different regio-specific absorption windows through a single system.
The therapeutic system of the invention is versatile regarding the types of drugs which can be incorporated therein; the drugs may be water soluble or insoluble, low dose or high dose.
The therapeutic system of the invention can provide continuous input of a drug in the gastric region, resulting in drug concentration profiles in a narrow range, and less fluctuations in drug levels, which is of special significance for narrow therapeutic index drugs.
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Various modifications of the system of the invention may be made without departing from the spirit or scope of the invention. The following non-limiting examples illustrate an embodiment of the invention and should not be construed to limit the scope of the invention.
EXAMPLE
Core Composition:

No. Ingredient Qty (mg/tab)
1 Lactose monohydrate 80.0
2 Microcrystalline cellulose 19.0
3 Magnesium stearate 1.0
Total 100.0 mg
Drug layer composition

No. Ingredient Qty (mg/tab)
1 Baclofen 10.0
2 polyvinyl pyrrolidone 3.0
Total 13.0
Lactose monohydrate and Microcrystalline cellulose were mixed together in a suitable blender. Magnesium stearate was further blended with the above powder mix. The mixture was compressed on a rotary tablet compression machine to form core tablets of 100 mg weight. The tablets were coated with an aqueous/ non-aqueous solution of vinylpyrrolidone-vinyl acetate copolymer. Further coating was applied with acrylate polymers/ co-polymers
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(Eudragit L-100 + Eudragit S-l00) with triethyl citrate as plasticizer in acetone/ isopropyl alcohol mixture. The coated tablets were subjected to heating at temperatures ranging from 40°C to 150°C. On expansion of the coated layer, the heat was removed and tablets were sprayed with an aqueous solution of baclofen and polyvinyl pyrrolidone.
Dated this 4th of September 2006


Documents:

1411-MUM-2006-ABSTRACT(14-9-2009).pdf

1411-mum-2006-abstract(25-4-2011).pdf

1411-mum-2006-abstract(3-9-2007).pdf

1411-mum-2006-abstract(amended)-(14-9-2009).pdf

1411-mum-2006-assignment(3-11-2006).pdf

1411-MUM-2006-CANCELLED PAGES(14-9-2009).pdf

1411-mum-2006-cancelled pages(16-4-2010).pdf

1411-MUM-2006-CLAIMS(14-9-2009).pdf

1411-MUM-2006-CLAIMS(AMENDED)-(16-04-2010).pdf

1411-mum-2006-claims(amended)-(16-4-2010).pdf

1411-mum-2006-claims(complete)-(3-9-2007).pdf

1411-mum-2006-claims(granted)-(25-4-2011).pdf

1411-mum-2006-claims(marked copy)-(15-4-2010).pdf

1411-mum-2006-correspondance-received.pdf

1411-MUM-2006-CORRESPONDENCE(1-4-2011).pdf

1411-MUM-2006-CORRESPONDENCE(13-3-2009).pdf

1411-mum-2006-correspondence(15-4-2010).pdf

1411-MUM-2006-CORRESPONDENCE(18-8-2009).pdf

1411-MUM-2006-CORRESPONDENCE(20-2-2012).pdf

1411-MUM-2006-CORRESPONDENCE(24-2-2010).pdf

1411-MUM-2006-CORRESPONDENCE(27-10-2008).pdf

1411-MUM-2006-CORRESPONDENCE(29-3-2011).pdf

1411-MUM-2006-CORRESPONDENCE(7-12-2010).pdf

1411-mum-2006-correspondence(ipo)-(26-4-2011).pdf

1411-MUM-2006-CORRESPONDENCE-(IPO)-(14-9-2009).pdf

1411-MUM-2006-DESCRIPTION(COMPLETE)-(14-9-2009).pdf

1411-mum-2006-description(complete)-(3-9-2007).pdf

1411-mum-2006-description(granted)-(25-4-2011).pdf

1411-MUM-2006-DRAWING(14-9-2009).pdf

1411-mum-2006-drawing(3-9-2007).pdf

1411-mum-2006-drawing(amended)-(14-9-2009).pdf

1411-mum-2006-drawing(granted)-(25-4-2011).pdf

1411-MUM-2006-FORM 1(14-9-2009).pdf

1411-MUM-2006-FORM 1(3-9-2007).pdf

1411-mum-2006-form 1(4-9-2006).pdf

1411-mum-2006-form 13(1)(3-9-2007).pdf

1411-mum-2006-form 13(2)(3-9-2007).pdf

1411-MUM-2006-FORM 13(20-2-2012).pdf

1411-mum-2006-form 13(3)(3-9-2007).pdf

1411-mum-2006-form 13(4)(3-9-2007).pdf

1411-mum-2006-form 13(5)(3-9-2007).pdf

1411-mum-2006-form 18(7-9-2007).pdf

1411-mum-2006-form 2(complete)-(3-9-2007).pdf

1411-mum-2006-form 2(granted)-(25-4-2011).pdf

1411-MUM-2006-FORM 2(TITLE PAGE)-(14-9-2009).pdf

1411-mum-2006-form 2(title page)-(complete)-(3-9-2007).pdf

1411-mum-2006-form 2(title page)-(granted)-(25-4-2011).pdf

1411-mum-2006-form 2(title page)-(provisional)-(4-9-2006).pdf

1411-MUM-2006-FORM 3(13-3-2009).pdf

1411-MUM-2006-FORM 3(14-9-2009).pdf

1411-MUM-2006-FORM 3(18-8-2009).pdf

1411-MUM-2006-FORM 3(24-2-2010).pdf

1411-MUM-2006-FORM 3(27-10-2008).pdf

1411-MUM-2006-FORM 3(29-3-2011).pdf

1411-mum-2006-form 3(3-9-2007).pdf

1411-mum-2006-form 3(4-9-2006).pdf

1411-mum-2006-form 5(14-9-2009).pdf

1411-mum-2006-form 5(3-9-2007).pdf

1411-mum-2006-form 5(4-9-2006).pdf

1411-MUM-2006-FORM PCT-IPEA-409(29-3-2011).pdf

1411-MUM-2006-FORM PCT-ISA-210(29-3-2011).pdf

1411-mum-2006-form-2.doc

1411-MUM-2006-OTHER DOCUMENT(13-3-2009).pdf

1411-MUM-2006-PCT-IPEA-409(13-3-2009).pdf

1411-MUM-2006-PCT-ISA-237(27-10-2008).pdf

1411-MUM-2006-PETITION UNDER RULE 137(29-3-2011).pdf

1411-MUM-2006-PUBLICATION IN THE CHILEAN GAZETTE(27-10-2008).pdf

1411-MUM-2006-REPLY TO EXAMINATION REPORT(14-9-2009).pdf

1411-MUM-2006-REPLY TO EXAMINATION REPORT(16-04-2010).pdf

1411-mum-2006-specification(amended)-(14-9-2009).pdf

1411-MUM-2006-WO INTERNATIONAL PUBLICATION REPORT A3(27-10-2008).pdf

1411-mum-description (provisional).pdf

1411-mum-form-1.pdf

1411-mum-form-2.pdf

1411-mum-form-26.pdf

1411-mum-form-3.pdf

1411-mum-form-5.pdf


Patent Number 247582
Indian Patent Application Number 1411/MUM/2006
PG Journal Number 17/2011
Publication Date 29-Apr-2011
Grant Date 25-Apr-2011
Date of Filing 04-Sep-2006
Name of Patentee PANACEA BIOTEC LTD.
Applicant Address 201, Samarpan Complex, New-Link Road, Chakala, Andheri (E), Mumbai 400099, Maharashtra, India
Inventors:
# Inventor's Name Inventor's Address
1 SINGH, AMARJIT 201, Samarpan Complex, New-Link Road, Chakala, Andheri (E), Mumbai 400099, Maharashtra, India
2 SINGH, SARABJIT 201, Samarpan Complex, New-Link Road, Chakata, Andheri (E), Mumbai 400099, Maharashtra, India
3 TANDALE, RAJENDRA 201, Samarpan Complex, New-Link Road, Chakala, Andheri (E), Mumbai 400099, Maharashtra, India
4 PUTHLI, SHIVANAND 201, Samarpan Complex, New-Link Road, Chakala, Andheri (E), Mumbai 400099, Maharashtra, India
PCT International Classification Number A61K9/22
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA