Title of Invention

A Process for preparation of a synergistic tablet composition useful for extended release of isosorbitol mononitrate

Abstract A novel pharmaceutical composition useful for extended release of isosorbide mononitrate ro an environment of use is disclosed. The tablet core composition comprising isosorbide mononitrate is surrounded by a rate controlling membrane comprising of a sernipenneable membrane-forming polymer, permeable membrane forming polymer, and at least one plasticizer capable of modulating the film formation properties of the polymers.
Full Text The present invention relates to a tablet composition useful for extended release of isosorbide mononitrate.
The invention pertains a pharmaceutical composition useful for extended release of isosorbide mononitrate to an environment of use. More specifically, the present invention relates to a novel pharmaceutical composition for extended release of isosorbide mononitrate, which operates on the principles of diffusion, osmotic pressure, or a combination of both. The pharmaceutical composition, in the present invention, comprises of tablet core of isosorbide mononitrate, polyvinyl pyrrolidone, osmagents, and other conventional excipients. The tablet core is coated with a rate controlling membrane wall, which is made up of a semipermeable and permeable membrane forming polymers.
Isosorbide 5 mononitrate (ISMN) is an active metabolite of isosorbide dimtrate and acts by relaxing the smooth muscles of the cardiovascular system. It is indicated for the treatment of the angina pectoris arising from coronary insufficiency. As other nitro derivatives, ISMN causes, in the greater portion of treated subjects, undesired effects such as headache, cutaneous blood-vessel dilation, and somnolence. ISMN has been formulated in a number of different ways so as to allow either immediate release or extended release of the drug. The use of extended release formulation will provide a more uniform plasma concentration of ISMN for a definite period of time and will tend to avoid the peak and trough effects associated with immediate release formulations. The frequency of daily administration will be reduced and a uniform plasma concentration for a definite period of time will avoid any development of tolerance, resulting in enhanced patient compliance. All the above side effects of ISMN and the fact that the half-life of
the drug is around 4 to 5 hours, the advantages of a pharmaceutical composition for extended release of ISMN, appear evident.
However, ISMN has certain drawbacks, which make it difficult to formulate it in a extended-release dosage form, namely: a static electricity phenomenon, which makes any dry mixing almost impossible when it is processed alone in a dry form, a sublimation phenomenon, i.e., transition from a solid to gas under certain conditions encountered during processing, and a very high aqueous solubility.
There are number of controlled release dosage forms available commercially that can be used for oral delivery of drugs. In matrix systems, the drug is embedded in a polymer matrix and the release takes place by partitioning of the drug into the poiymer matrix and the release medium. However, factors like pH, presence of food, and other physiological factors may affect drug release from matrix systems. Osmotic systems utilize the principles of osmotic pressure for the delivery of drugs. These systems typically consist of a tablet core of drug with or without an osmagents, coated with a rate controlling membrane. Delivery of drug takes place through an orifice that is created in the membrane using a mechanical or a laser drill.
Pharmaceutical compositions for extended delivery of ISMN, to the environment of use. are well known in the prior art. Reference may be made to U.S. Patent No. 5,851,555, which discloses a pharmaceutical composition containing ISMN along with an optional inert carrier, a cellulosic polymer, and a lipophilic ingredient. ISMN is mixed with the inert carrier, cellulosic polymer, lipophilic ingredient, and other excipients The mixture is then heated at 70°C to 90°C for about 3 hours with stirring at 1 -hour intervals. This blend is then chopped in a high shear mixer, which is then cooled and milled to get a
solid dispersion in a granulate form. The mixture so obtained is then blended with additional amounts of cellulosic polymers, fillers, and lubricants and compressed into a dosage unit. U.S. Patent No. 5,453,283 discloses delayed release oral dosage forms wherein the drug is melt-blended with a thermoplastic material (preferably polyvinyl acetate) and a "structure former" (e.g., lactose). Drug along with an inert carrier and polyvinyl acetate is sifted and heated to about 80°C. The melt is then kneaded with a pestle and after further processing, which involves hardening of the material and cutting into small pieces, the material is then mixed with other excipients and compressed m the form of tablets. Reference may also be made to Pharmazie, Vol. 47, pp 465-466 and vol. Vol. 48, pp 611-613, wherein microballs of ISMN are prepared by dropping 86% aqueous mixture of ISMN-sorbitol-mannitol into liquid paraffin at the temperature of 423 K. The cores are then fractionated by means of sieves and microballs having diameter of 0.8 to 2.0 mm are coated with a membrane wall. Though the above compositions are useful for extended delivery of ISMN, their use can be limited because of number of manufacturing steps involved and difficulty in scaling up the technology to commercial scale.
U.S. Patent No. 5,869,094 discloses a pharmaceutical composition in which inert sugar beads are first coated with a depot layer (containing ISMN along with PVP, hydroxypropyl methylcellulose, talc, and polyethylene glycol). Immediately after the application of depot layer, remaining coating suspension (without drug) is applied to the beads. The beads are further coated with a retarding coat containing ethyl cellulose and polymethacrylate. This composition can be useful for extended delivery of ISMN but the number of coating steps involved in the manufacturing can limit its commercial use.
Moreover, the drug is present in the coating composition only and applied by spraying, therefore, slight variation in the amount of coating applied can affect the drug content of the formulation, which could result in variable drug input to the body.
U.S. Patent No. 4,812,316 discloses a pharmaceutical composition in which ISMN is mixed with polyvinyl pyrrolidone (PVP) to form a solid solution. This solution is then mixed with hydroxypropyl methylcellulose (HPMC) and other additives. The ratio of polymers (PVP plus HPMC) to drug is 1:5 to 5:1. PCT Patent Application W.O. 98/05306 discloses a pharmaceutical composition in which ISMN is granulated with a solution of PVP and the dry granules are blended with a cellulose-based polymer U.S. Patent No. 5,334,393 discloses a pharmaceutical composition for controlled release of 5-ISMN, which is made by combining drug particles having four or more different sizes with a swellable hydrophilic polymer. The swellable polymers may be selected from natural gums, alginic derivatives, methylcellulose, carboxymethylcellulose, hydroxypropyl cellulose, and/or ethylhydroxypropyl cellulose. All the compositions that have been described above are based on matrix technology.
In the light of the above discussion, it will be readily appreciated by those versed in the subject art that a critical need exists for a novel pharmaceutical composition useful for extended release of ISMN, which is simple in design, involves less number of manufacturing steps, and is easily amenable to mass production.
The main object of the present invention is to provide a novel pharmaceutical composition useful for extended release of ISMN, which obviates the drawbacks as detailed above.
Another object of the present invention is to provide a novel pharmaceutical composition that contains ISMN along with an inert carrier, PVP, and osmotically effective solutes or osmagents that are soluble in water and capable of exhibiting an osmotic pressure gradient across the wall against the external fluids.
Yet another object of the present invention is to provide a novel pharmaceutical composition, which comprises of a rate controlling membrane consisting of semipermeable and permeable membrane forming polymers that surrounds the tablet core compartment consisting of ISMN along with an inert carrier, PVP, and osmagents.
Yet another object of the invention is to provide a novel pharmaceutical composition comprising of a rate controlling membrane that surrounds the core compartment, which rate controlling membrane comprises of a semipermeable membrane forming polymer, which is permeable to the aqueous fluids but is substantially impermeable to the components of the core, and a permeable membrane forming polymer, which is permeable to aqueous fluids and at least one of the components of the core.
Still another object of the invention is to provide a novel pharmaceutical composition comprising of a rate controlling membrane surrounding the core compartment, where the rate controlling membrane comprises of a semipermeable membrane forming polymer, permeable membrane forming polymer, and at leasi one plasticizer capable of modulating the film formation properties of the polymers.
Yet another object of the present invention is to provide a novel pharmaceutical composition, from where the drug release occurs- through the mechanisms of diffusion.
osmotic pumping, or a combination of both and is simple in design and amenable to mass
oroduction.
Other objects, features and advantages of the invention will be more apparent to those versed in
the dispensing art from reading the detailed description of the specification, taken in conjunction
with the drawing figures and accompanying claims.
Thus, a novel pharmaceutical composition, consisting of a tablet core of ISMN, an inert carrier,
PVP, and osmagent, is prepared and coated with a membrane wall forming composition consisting
of a semipermeable membrane forming polymer, permeable membrane forming polymer, and
plasticizer(s). The pharmaceutical composition, in the present invention, is simple, easy to
manufacture, and easily amenable to mass production as compared to prior art and yet effective in
extended release of ISMN.
In the drawings accompanying this specification, figure 1 represents release profile of ISMN from
formulations made in example 1 in comparison with marketed extended release formulation
Figure 2 represents release profile of ISMN from formulations made in example 2 in comparison
with marketed extended release formulation
Figure 3 represents release profile of ISMN from formulations made in example 3 in comparison
with marketed extended release formulation
Figure 4 represents release profile of ISMN from formulations made in example 4 in comparison
with marketed extended release formulation
Accordingly, the present invention provides a process for preparation a tablet composition useful
for extended release of isosorbide mononitrate, the said tablet comprising : a core comprising a
drug 5 to 50 w/w of isosorbide mononitrate, 10 to 60 w/w of an inert carrier, such as herein
described 5 to 40 w/w of polyvinyl pyrrolidone ( PVP ), and 5 to 60 w/w of osmotically effective
solutes that are soluble in water and capable of exhibiting an osmotic pressure gradient across
the wall against the external fluids, the said process comprises dry blending of drug as defined
above and inert carrier such as herein described with PVP and osmagents , and mixed with
conventional excipients so as to form core tablet , optionally, the core composition can be Prepared by the techniques of slugging or wet granulation wherein the drug is blended with the other excipients using water or an organic consolvent such as isopropyi alcohol/methylene chloride, 80 / 20, V/V as the granulation fluid, the obtained granules are dried and passed through a 22 - mesh screen and blended with lubricant and glidant in a mixer, and compressed followed by coating with a membrane wall such as herein described to get the desired tablet composition .
In an embodiment the membrane wall surrounding the said core comprising and prepared from a semipermeable membrane forming polymer that is, at least in part, permeable to water but substantially impermeable to the core components, a polymer material that is soluble in water and permeable to water and at least one of the components of the core, having ratio ranging from 9 : 1 to 4 : 6 and 0.1 to 60 %, by weight, of at least one plasticizer, based on the total weight of dry polymers.
The composition is synergistic in nature and no chemical reaction is involved in the ingredients of the composition.
In an embodiment of the present invention, pharmaceutical composition consists of a tablet core surrounded by a rate controlling membrane. The tablet core consists of ISMN, and inert carrier, PVP, and osmotically effective agents or osmagents that are soluble in water and capable of exhibiting an osmotic pressure gradient across the wall against the external fluids. Drug, inert carrier, PVP, and osmagents may be combined with other conventional excipients as needed to from a core compartment of the pharmaceutical composition. The core compartment is surrounded by a rate controlling membrane that consists of semipermeable membrane forming polymer, permeable membrane forming polymer, and at least one plasticizer that is capable of improving film formation properties of the polymers. The semipermeable membrane forming polymer is permeable to aqueous fluids but is substantially impermeable to the components of the
core. The permeable membrane forming polymer is permeable to aqueous fluids and at least one of the components of the core. In operation, the core compartment imbibes aqueous fluids from the surrounding environment across the rate controlling membrane. The dissolved drug is released at a controlled rate across the membrane wall, permeability of which can be modulated by proper choice of polymers and plasticizers and by varying the ratio of semipermeable to permeable forming polymer.
Special handling considerations for ISMN require premixing of the drug with an inert carrier separately. The inert carrier used is typically a non-reactive excipient, which is generally dry blended with ISMN. Suitable carriers include cellulose and saccharides, such as lactose, mannitol, etc.
There are a variety of pharmaceutical compositions that incorporates osmotically effective solutes in the device core. These agents are capable of causing an osmotic pressure gradient across the device wall and imbibe fluid into the device. The osmotically effective compound, also known as osmagent, which can be used in the present invention may include organic and inorganic compounds or solutes that exhibit an osmotic pressure gradient across the membrane, when placed in an aqueous environment. Osmotically effective compounds useful for this purpose may include magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, calcium bicarbonate, sodium sulfate, calcium sulfate, potassium acid phosphate, calcium lactate, mannitol, urea, inositol, sorbitol, magnesium succinate, tartaric acid, carbohydrates such as raffinose, sucrose, glucose, lactose, and mixtures of above said osmagents. A specially preferred osmagent is sodium chloride.
Materials that can be used to form the semipermeable membrane may include cellulose esters selected from cellulose acetate, cellulose acetate acetoacetate, cellulose acetate benzoate, cellulose acetate butyrate, cellulose acetate chloroacetate, cellulose acetate palmitate, cellulose acetate propionate, cellulose acetate succinate, cellulose acetate sulfate, cellulose acetate valerate, cellulose benzoate, cellulose nitrate, cellulose nitrobenzoate, cellulose triacetate; cellulose ethers such as ethyl cellulose, ethyl cellulose sulfate, or ethylcellulose dimethylsulfamate; polysulfones, polyethersulfones, polyurethanes, polyvinyl acetates, polyamides, polysiloxanes, polyesters, polyalkenes such as polyethylene, ethylene vinyl alcohol copolymer, polypropylene, polyvinyl chloride, polyurethane, polycarbonate, polyethylene, shellac, polymers of acrylic and methacrylic acid and esters thereof, and mixtures of above said polymers. A specially preferred semipermeable membrane-forming polymer is ethyl cellulose.
Materials used to form the permeable membrane may include polyvinyl alcohol, polyvinyl pyrrolidone, alkyl and hydroxyalkyl celluloses such as methyl cellulose, hydroxypropyl methylcellulose, hydroxybutyl methylcellulose, hydroxypropyl cellulose, sodium carboxy methyl cellulose, hydroxyethyl methylcellulose, and hydroxyethyl cellulose; cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polymers of acrylic and methacrylic acid and esters thereof, and mixtures of above said polymers. A specially preferred permeable membrane-forming polymer is polyvinyl pyrrolidone.
Exemplary plasticizers suitable for the present invention may include plasticizer that lowers the temperature of the second-order phase transition of the wall or the elastic modulus thereof, and also increase the workability of the wall and its flexibility. Plasticizers may increase or decrease the permeability of the wall to fluids including
water and aqueous solutions. Plasticizers suitable for the present invention include both cyclic and acyclic plasticizers. Typical plasticizers are those selected from the group consisting of phthalates, phosphates, citrates, adipates, tartrates, sebacates, succinates, glycolates, glycerolates, benzoates, myristicates, polyethylene glycols, polypropylene glycols, and halogenated phenyls. Depending on the particular plasticizer, amounts ranging from 0.1 to about 60% of the plasticizer can be used based upon the total weight of the polymer. Exemplary plasticizers for the present invention include dialkyl phthalates, dicyclalkyl phthalates, diaryl phthalates, and mixed alkylaryl as represented by dimethyl phthalate, dipropyl phthalate, dibutyl phthalate, dioctyl phthalate. di-isopropyl phthalate, diamyl phthalate: alkyl and aryl phosphates such as triethyl phosphate, tributyl phosphate, trioctyl phosphate, and triphenyl phosphate; alkyl citrate and citrate esters such as tributyl citrate, triethyl citrate, and acetyl triethyl citrate; alkyl adipates such as dioctyl adipate and diethyl adipate; dialkyl tartrates such as diethyl tartrate and dibutyl tartrate; sebacates such as diethyl sebacate, dibutyl sebacate, and dipropyl sebacate; alkyl glycolates, alkyl glycerolates, glycol esters and glycerol esters such as glycerol diacetate, glycerol triacetate, glycerol monolactate diacetate, ethylene glycol diacetate, ethylene glycol dibutyrate, and triethylene glycol dibutyrate. Other plasticizers include polyethylene glycols, camphor, liquid sorbitol, triacetin, castor oil, olive oil, sesame oil, substituted epoxides, and mixtures of above. A specially preferred plasticizer is propylene glycol.
It is generally desirable from a preparation standpoint to mix the polymer in a solvent system. Exemplary solvents suitable for manufacturing the wall of the instant delivery system may include inorganic and organic solvents that do not adverseiy harm
the core, wall, and the materials forming the final wall. The solvents broadly include members selected from the group consisting of aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic, aromatic, heterocyclic solvents and mixtures thereof. Water based latex forms of the suitable polymers also fall within the scope of the present invention. Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl ethyl ketone, methyl propyl ketone, n-hexane, ethyl lactate, n-heptane, ethylene glycol monoethyl acetate, methylene dichlonde, ethylene dichloride, propylene dichlonde, carbon tetrachloride, nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropyl ether, cyclohexane, cyclooctane, dimethylbromamide, benzene, toluene, water and mixtures thereof such as acetone and water, acetone and methanol, methylene dichloride and methanol.
The pharmaceutical composition, in the present invention, is manufactured by standard techniques of tableting and coating. For example, in one of the procedures the drug, inert carrier, PVP, and osmagents are dry blended. These components are then mixed with conventional excipients so as to form core tablet. Optionally, the core composition can be prepared by the techniques of slugging or wet granulation, hi wet granulation, the drug is blended with the other excipients using water or an organic cosolvent such as isopropyl alcohol/methylene chloride, 80/20, V/V as the granulation fluid. The wet granules are dried and passed through a 22-mesh screen and blended with lubricant and glidant in a mixer. The blend is then compressed in the form of a tablet. The compressed tablet is then coated with a membrane wall. The wall forming composition
can be applied using the techniques of press coating, spraying, dipping, or air suspension techniques. The wall surrounding the tablet core is prepared by using the mixture of semipermeable and permeable membrane forming polymers and it is possible to control the permeability of the membrane by varying the ratio of semipermeable and permeable polymers. In operation, the core compartment imbibes aqueous fluids from the surrounding environment across the rate controlling membrane. The dissolved drug is released at a controlled rate across the membrane wall. The novelty in the present invention is that a novel pharmaceutical composition, consisting of a tablet core of 1SMN, an inert carrier, PVP, and osmagent, is prepared and coated with a membrane wall forming composition consisting of a semipermeable membrane forming polymer, permeable membrane forming polymer, and plasticizer(s). Thus, the pharmaceutical composition, in the present invention, is simple, easy to manufacture, and easily amenable to mass production as compared to prior art and yet effective in extended release of ISMN.
EXAMPLES
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.
Example 1
Core tablets of ISMN were prepared as per the following formula
(Formula & Table Removed)
ISMN and spray dried lactose (Flow lac-100, Meggie, Germany) were mixed for 10 minutes. After passing this mixture through a 30-mesh sieve (BSS), PVP and sodium chloride (30-mesh passed) were added and the mixing continued for 10 additional minutes. To the mix. (>0-mesh passed magnesium stearate and aerosii were added and mixing continued for lo more minutes. The blend was compressed in the form of biconvex tablets having an average weight of 300 mg using a single stroke tablet punching machine (Cadmach GMS-15, India) having 9.00 mm round standard concave punches. 80 of these tablets were placed in a laboratory scale 10" perforated coater (Ganscoater-GAC 250. Gansons. India) along with 400 grams of filler tablets (tablets made using 7.00 mm round deep concave punches and containing microcrystalline cellulose, starch, dibasic calcium phosphate, magnesium stearate, and aerosii) and coated with a coating solution comprising of
(Table Removed)
The coating solution was prepared by adding ethyl cellulose (Ethocel standard 10 cp premium, Colorcon Asia Pvt. Lt., Mumbai) to the mixture of methylene chloride and ethanol. After the entire polymer was dissolved, PVP was added with continuous stirring. Finally, propylene glycol was added and thoroughly mixed to give the final coating solution. The filler and active tablets were placed in the coating pan and the heated air was passed through the tablet bed. The pan was rotated at 18-20 rpm. When the outlet air temperature reached 28° C, the coating solution was applied through the atomizing nozzle at the rate of 7-8 ml/minute with atomization at 1 Kg/Cm2. Sufficient coating solution was applied until a % weight increase of 4.21 % was achieved on the active tablets. 20 of the active tablets were withdrawn and coating continued until % weight increase of 5.19 % on active tablets was achieved. 20 of the tablets were removed and coating continued to achieve a weight gain of 7.61 % on the active tablets. 20 of the tablets were removed and coating continued to achieve a weight gain of 11.49 % The active tablets were dried in an oven for 16 hours at 50° C. The release studies of these tablets and marketed extended release formulations of ISMN (Imdur 60 mg, Astra Idl, India) was conducted in 900 ml of simulated intestinal fluid, pH 6.8, without enzymes using USP type 1 (basket) apparatus at 100 rpm. The samples were withdrawn periodically and analyzed by HPLC using C-18 column (Spherisorb, Waters, USA) at 220 nm using watenmethanol (80:20) as the mobile phase. The plot of percent drug released versus time is shown in figure 1.

The results shown in figure 1 depicts that the pharmaceutical compositions prepared in accordance with the present invention exhibits extended release of ISMN for prolonged period of time. In this example ethyl cellulose is a semipermeable membrane-forming polymer and PVP is a permeable membrane-forming polymer. It is evident from the figure that the drug release is affected by the percentage weight gain of polymer solution on the active tablets and it is possible to modulate the release as per the requirements by varying this membrane parameter.
Example 2
Example 1 was repeated except that the following membrane composition was used to explore the possibility of using PEG-4000 as a permeable membrane-forming polymer
(Table Removed)
The tablets were coated as described in example 1 and the coating continued until a weight gain of 9.72 % was achieved on the active tablets. The active tablets were dried in an oven for 16 hours at 50° C. The release profile of ISMN from the active tablets in comparison with Imdur tablets is shown in figure 2. It is evident that from the figure that
despite the slow release as compared to those containing PVP as a permeable membrane-forming polymer, the release of ISMN is controlled from the active tablets.
Example 3
Example 1 was repeated except that the following membrane composition was used to explore the possibility of using HPMC as a permeable membrane-forming polymer
The tablets were coated as described in example 1 and the coating continued until a weight gain of 9.49 % was achieved on the active tablets. The active tablets were dried in an oven for 16 hours at 50° C. The release profile of ISMN from the active tablets in comparison with Imdur tablets is shown in figure 3. It is evident that from the figure that despite the slow release as compared to those containing PVP or PEG-4000 as a peraieable membrane-forming polymer, the release of ISMN is controlled from the active tablets.

(Table Removed)
Example 4
This study was performed to study the effect of level of permeable membrane forming polymer on the release of ISMN from the formulations. The tablets containing ISMN were coated with the coating compositions given in table 1
Table 1
(Table Removed)
The tablets were coated as described in example 1 and the coating continued until an approximate weight gain of 10.00 % was achieved on the active tablets. The tablets were dried in an oven for 16 hours at 50° C. The release profile of ISMN from the active tablets in comparison with Imdur tablets is shown in figure 4. It is clearly evident from the figure that the release of ISMN increases as the level of permeable membrane forming polymer increases and thus, it is possible to control the release of ISMN by varying the level of permeable membrane forming polymer.
The main advantages of the present invention are
1. The pharmaceutical composition can be used for extended delivery of isosorbide mononitrate.
2. The release of ISMN from the pharmaceutical composition can be easily adjusted by modulating the membrane variables such as, type and level of permeable-membrane forming polymer and total weight of the membrane wall applied.
3. The pharmaceutical composition is simple to manufacture, involves less number of manufacturing steps, and is easily amenable to mass production.




Claim:
1 A process for preparation a synergistic tablet composition useful for extended release of isosorbide mononitrate, the said tablet composition comprising : a drug 5 to 50 w/w of isosorbide mononitrate, 10 to 60 w/w of an inert carrier, such as herein described 5 to 40 w/w of polyvinyl pyrrolidone ( PVP ), and 5 to 60 w/w of osmotically effective solutes that are soluble in water and capable of exhibiting an osmotic pressure gradient across the wall against the external fluids, the said process comprises dry blending of drug as defined above and inert carrier such as herein described with PVP and osmagents , and mixed with conventional excipients so as to form core tablet.
2 A process for preparation of synergistic tablet composition as clamed in claim 1, wherein said inert carrier is selected from saccharide lactose, mannitol, or a mixture thereof and cellulose.
3. A process for preparation of synergistic tablet composition as claimed in claim 1-2, from wherein Osmotically effective solute is selected from magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, calcium bicarbonate, sodium sulfate, calcium sulfate, potassium acid phosphate, calcium lactate, mannitol, urea, inositol, sorbitol, magnesium succinate, tartaric acid , carbohydrates such as raffinose, sucrose, glucose, lactose, and mixtures of above said
osmagents. A specially preferred osmagent is sodium chloride.
4 A process for preparation a synergistic tablet composition useful for extended release of isosorbide mononitrate substantially as herein described with references to the examples and drawings accompanying this specification.

Documents:

698-del-2001-abstract.pdf

698-del-2001-claims.pdf

698-del-2001-complete specification (granded).pdf

698-del-2001-correspondence-others.pdf

698-del-2001-correspondence-po.pdf

698-del-2001-description (complete).pdf

698-del-2001-drawings.pdf

698-del-2001-form-1.pdf

698-del-2001-form-2.pdf

698-del-2001-form-3.pdf

698-del-2001-form-4.pdf


Patent Number 199639
Indian Patent Application Number 698/DEL/2001
PG Journal Number 29/2008
Publication Date 26-Sep-2008
Grant Date 08-Dec-2006
Date of Filing 22-Jun-2001
Name of Patentee Council of Scientific & Industrial Research,
Applicant Address RAFI MARG,NEW DELHI-110001,INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 Sanjay Garg National Institute of Pharmaceutical Education and Research (NIPER) Sector-67, SAS Nagar,Punjab,India.
2 Ranjan Kumar Verma National Institute of Pharmaceutical Education and Research (NIPER) Sector-67, SAS Nagar,Punjab,India.
3 Chaman Lal Kaul National Institute of Pharmaceutical Education and Research (NIPER) Sector-67, SAS Nagar,Punjab,India.
PCT International Classification Number A 61K-31/00,424/464
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA