Title of Invention

A PROCESS FOR THE MANUFACTURING OF FLOATING SWELLABLE AND BIOADHESIVE SUSTAINED RELEASE DOSAGE FORMS

Abstract A process for the manufacturing of floating, swellable and bioadhesive sustained release oral dosage form preferably once daily for oral administration in humans for the controlled release of drugs comprising the steps of: (i). mixing of all the ingredients by conventional process, (ii). granulating by conventional process and (iii). compressing into dosages having pharmaceutically effective amount of drugs such as ofloxacin or its pharmaceutically acceptable salts and sustained release composition comprising; (a). 0.2 to 50% gel forming and bioadhesive fiber such as psyllium husk, (b). 0.5 to 40% swelling agent such as crosslinked polyvinyl pyrrolidone which is superdisintegrant, (c). 0.5 to 25% channeling agent such as cyclodextrin, p-cyclodextrin or eudragit E-100, (d). 0.5 to 30% hydrophilic polymer such as hydroxypropyl methyl cellulose, (e). 1 to 25% gas generating agent such as sodium bicarbonate, (f). 1 to 10% polyvinyl pyrrolidone, (g). 1 to 5% excipients and (h). optionally 2 to 25% carbopol 97IP.
Full Text FORM 2
THE PATENTS ACT 1970 COMPLETE SPECIFICATION
(See Section 10)
TITLE A process for the manufacturing of floating, swellable and bioadhesive
sustained release dosage forms




APPLICANT
Dr. Vavia Pradeep Ratilal
Pharmaceutical Sciences Division, Mumbai University Institute of Chemical Technology, N. P. Marg, Matunga, Mumbai-400 019.

The following specification particularly describes the nature of the invention and the manner in which it is to be performed:-

26 AUG 2002

FIELD OF INVENTION
The present invention is related to a process for manufacture of an oral sustained release tablet dosage form comprising an effective amount of drug or its pharmaceutically acceptable salts in a floating, swellable and bioadhesive carrier composition. The present invention is in the field of an oral sustained drug delivery system preferably once daily formulation. The present invention is particularly related to a process for manufacture of an oral sustained release tablet dosage form having drugs, in a floating, swellable and bioadhesive carrier composition, which have an absorption window in the specific regions of stomach or intestine.
BACKGROUND OF THE INVENTION
By "sustained release" it is meant for the purpose of the invention that the therapeutically active drug is released from the formulation at a sustained rate such that therapeutically beneficial blood levels (but below toxic levels) of the drug are maintained over an extended period of time, e.g., providing a 6 hour, 12 hour or 24 hour dosage form.
Sustained drug delivery results in optimum therapy, and not only reduces the frequency of dosing, but may also reduce the severity and frequency of side effects. Considerable efforts have been made in the last decades to develop new pharmaceutically viable and therapeutically effective sustained drug delivery systems. The progress in the orally administered sustained drug delivery systems being relevant to the field of invention is reviewed below.


The oral sustained drug delivery systems are based on different modes of operation, such as dissolution controlled systems, diffusion controlled systems, ion-exchange resins, osmotically controlled systems, erodible matrix systems, pH-independent formulations, swelling controlled systems, bioadhesive controlled systems and the like.
Such oral sustained drug delivery systems are expected to deliver the drug at a constant and reproducible rate in spite of the varying conditions in the stomach such as pH and agitation. In spite of considerable efforts made to design oral sustained drug delivery systems in the last decade, there is success only in a few individual drugs. One of the reasons for this is not all drugs are absorbed uniformly in the gastrointestinal tract; the dosage form gets rapidly transported from more absorptive upper regions of the intestine to lower regions where the drug is less well absorbed. More particularly, in instances where a drug has a clear cut "absorption window," i.e. the drug is absorbed only from specific regions of the stomach or upper parts of the small intestine, it may not be completely absorbed when administered in the form of a typical oral sustained drug delivery system. For a drug having such an "absorption window," it becomes necessary to retain the drug in the upper parts of the gastrointestinal tract for a long period of time. Some work done in this direction is reviewed below:
U.S. 4,777,033 (1988) discloses an oral controlled release pharmaceutical composition comprising a lower alkyl ether of cellulose, polyacrylic acid or its pharmaceutically acceptable salt, a drug, and an effective amount of an effervescent foaming agent.
The compositions exemplified therein are either in the form of granules, granules filled in capsules or tablets that break up into granules when subjected to the dissolution test specified in the Japanese Pharmacopoeia.


This system is not useful for i. drugs having an absorption window.
Since granules usually release drug in a shorter gastrointestinal transit time than intact tablets, this system does not provide the desired prolonged retention time at the site of absorption. Further, upon disintegration, a tablet of this invention yields a large number of granules and the multiparticulate systems, such as pellets or granules, are distributed over the length of the gastrointestinal tract releasing the drug at these different locations and hence not suitable for drugs having an absorption window, ii. highly water soluble drugs,
As the amount of drug in such formulations is several times more than that in a conventional formulation, this system is not useful for highly water-soluble drugs. This is because drugs are released with a dose dumping effect.
J P 63-14715 (1988) discloses a slow releasing pharmaceutical oral
formulation comprising a high viscosity water-soluble polymer, cross-linked
insoluble polyvinylpyrrolidone and a foaming component.
When a high dose medicament is to be incorporated into tablets based on
this system, the size of the tablets would be large and not suitable for oral
administration.
U.S. 5,651,985 (1997) discloses a composition comprising a pharmacologically active compound, a pharmaceuticalfy acceptable auxiliary, polyvinylpyrrolidone and a methacrylic acid polymer having an acidic number between 100 and 1200 mg of KOH/g of polymer solid substance. Optionally, the composition also contains a gas forming additive.


The composition absorbs many times its weight of acidic water and forms a highly swollen gel of high mechanical and dimensional stability. The drug is released by erosion of outer layer of the gel, and the inner layer gets swollen. To prevent the passage of the tablet through the pylorus for a relatively long time, 30%-90% by weight of the composition comprises the polymers. This tablet would be large for a drug that needs a larger dose, and inconvenient for oral administration.
U.S. 6261601 (2001) discloses a pharmaceutical composition in the form of tablets or capsules provides a combination of temporal and spatial control of drug delivery to a patient for effective therapeutic results.
The pharmaceutical composition comprises a drug, a gas-generating component, a swelling agent, a viscolyzing agent and optionally a gel-forming polymer.
The swelling agent belongs to a class of compounds known as superdisintegrants (e.g., cross-linked polyvinylpyrrolidone). The viscolyzing agent initially and the gel forming polymer thereafter form a hydrated gel matrix which entraps the gas, causing the tablet or capsule to be retained in the stomach or upper part of the small intestine (spatial control). At the same time, the hydrated gel matrix creates a tortuous diffusion path for the drug, resulting in sustained release of the drug (temporal control).
A once daily tablet formulation for oral administration in humans for the controlled release of ciprofloxacin in the stomach or upper part of the small intestine comprises a pharmaceutically effective amount of ciprofloxacin, about 0.2% to about 0.5% sodium alginate, about 0.5 to about 2.0% xanthan


gum, about 10.0% to about 25% sodium bicarbonate, and about 5.0% to
about 20% cross-linked polyvinylpyrrolidone, said percentages being w/w of
the composition, and wherein the weight ratio of sodium alginate to xanthan
gum is between about 1:1 to about 1:10.
In gas generating systems, gas-generating component reacts with gastric acid to release the gas, which is entrapped in the matrix to reduce density and to cause floating. This US patent describes controlled release tablet based on a single drug ciprofloxacin and is based on a system that floats because of gas generated in the system on reaching acid environment.
US 6,312,726 (2001) describes a gastric retaining preparation having a configuration entirely different from that of the conventional ones. It comprises a swollen molding having a mesh-like cross-section and an apparent density of less than 1, containing an acid-resistant polymer compound as a predominant component as well as at least an auxiliary blowing agent and a drug substance. The molding can be produced by using a multi-screw extruder.
Recently B.N. Singh and K.H. Kim have reviewed the floating drug delivery systems, Journal of controlled release, 63(2000), 235-259. US 5096714 (1992) describes a prolonged-release unit dosage formulation or pharmaceutical composition, preferably in tablet form. The composition consists essentially of a gel-forming dietary fiber, a biologically-absorbable drug or other active therapeutic agent, and certain specific disintegrants, namely, a physiologically-acceptable edible acid and a mineral salt which releases a physiologically-acceptable gas upon ingestion, preferably carbon dioxide, e.g., a mineral carbonate or bicarbonate, and advantageously


dextrose or like soluble sugar. The dietary fiber-containing composition, when compressed into a tablet together with the drug and the specific disintegrants, provides a unique and efficient prolonged-action drug-delivery system. This system is not suitable for the drugs having an absorption window in the upper part of the gastrointestinal tract. This system is also not useful for the once daily sustained release formulations. US 5,445,826 (1995) describes a prolonged-release unit dosage formulation or pharmaceutical composition, preferably in tablet form. The composition consists essentially of a gel-forming fiber, preferably hydrocolloid-coated, a biologically-absorbable drug or other active therapeutic agent which is also preferably hydrocolloid-coated, a mineral salt which releases a physiologically-acceptable gas upon ingestion, preferably carbon dioxide, e.g., a mineral carbonate or bicarbonate, and optionally an organic or phosphoric acid and a dextrose or like soluble sugar. The fiber-containing composition, when in the form of a tablet or other unit dosage form together with the drug or agent and the stated disintegrants, provides a unique, efficient and controllable prolonged-action drug-delivery system. This system is not suitable for the drugs having an absorption window in the upper part of the gastrointestinal tract. This system is also not useful for the once daily-sustained release formulations.
US 5,445,831(1995) describes psyllium husk comprising particle sizes distributed such that: less than about 15% is larger than about 80 mesh, at least about 45% is within the range of from about 80 mesh to about 200 mesh, and less than about 40% is smaller than about 200 mesh. In addition, psyllium-containing products for oral administration comprising small particle size psyllium husk according to the present invention are described. This system is not useful for the once daily sustained release formulations.


US 6,251,421 (2001) describes orally administrable pharmaceutical compositions containing an inhibitor of gastrointestinal lipase, and at least one compound selected from the group consisting of psyllium husk, its seeds and leaves thereof. Methods are provided for preventing and treating anal leakage of oil in a patient to whom a composition containing an inhibitor of gastrointestinal lipase is orally administered.
US 6,312,730 (2001) describes a rapidly dispersible powder having use as a laxative and fiber supplement, comprising psyllium particles coated with gum arabic. The present invention also includes a method for making the powder that includes providing an effective quantity of gum arabic to a fluidized bed having the psyllium particles to make the rapidly dispersible powder. The present invention further includes a method for making a constipation treatment and a treatment for fiber supplementation.
US 6,322,772 (2001) describes a dentifrice form consisting of a dry compound of sodium bicarbonate as an oral bactericidal agent and oral antacid, psyllium husk fiber as a delivery system being an absorbent expansive binder and a flavoring agent. The dentifrice form is then placed in a porous dental mouth tray which is lined with a permeable matrix moistened with potable water. The dentifrice form in the tray is then moistened with potable water and the tray with the moistened dentifrice form is inserted into the oral cavity and placed against the upper or lower dental arch so as to cause the dentifrice form to be in contact with the teeth and gums of the respective arch for a period of seven minutes. The process is then repeated for the remaining dental arch.


WO 02/24203 A2 (International publication number with Indian patent application number 856/DEL/2000) describes a pharmaceutical composition in the form of oral controlled release solid dosage form comprising an effective amount of drug, or its pharmaceutically suitable salts. It also relates to a pharmaceutical composition that is suitable for once-a-day dosing regimen. The present invention provide an oral controlled drug delivery system of drug which- a), comprises carboxyvinyl polymer (carbopol 971P) that gelatinizes in the alkaline environment and regulates the release of drug.
b). comprises hydrophilic polymers that swell upon imbibition of water and further provides controlled release of drug.
WO 02/41876 describes a pharmaceutical composition for controlled release of an active ingredient, said composition comprising a controlled release matrix comprising a beta lactam antibiotic or their pharmaceutically acceptable hydrates, salts or esters as the active ingredient, and a mixture of hydrophilic polymers, said hydrophilic polymers being selected from the group consisting of at least one sodium alginate and at least one xanthan gum; and optionally probenecid as either immediate release or controlled release part.
US Patent 5096714 (1992) and US Patent 5292518 (1994) describe a prolonged-release unit dosage formulation or pharmaceutical composition, preferably in tablet form, is the composition consists essentially of a gel-forming dietary fiber, a biologically-absorbable drug or other active therapeutic agent, and certain specific disintegrants, namely, a physiologically-acceptable edible acid and a mineral salt [US Patent 5292518 (1994) describes the same mineral salts alone and not the


physiologically-acceptable edible acid] which releases a physiologically-acceptable gas upon ingestion, preferably carbon dioxide, e.g., a mineral carbonate or bicarbonate, and advantageously dextrose or like soluble sugar. The dietary fiber-containing composition, when compressed into a tablet together with the drug and the specific disintegrants, provides a unique and efficient prolonged-action drug-delivery system.
According to the invention, when a biological liquid begins to penetrate or wick into the prolonged-release unit dosage formulation, it dissolves the acid and mineral salt present therein, which react together to cause a rapid evolution of gas, e.g., carbon dioxide, which cannot be effected using either stomach acid alone or the mineral salt alone. This rapid evolution of gas breaks up the prolonged-release unit dosage form, e.g., tablet, granule, capsule, lozenge, or the like, before a surface layer of gel can form around the unit dosage form, especially a tablet, from the normal reaction of the gel-forming dietary fiber, which surface layer of gel would seal the unit dosage form off from further hydration and disintegration. Thus gas penetrates and modulates the film of gel produced from the gel-forming dietary fiber and thus assists in the proper disintegration of the unit dosage form. The above mentioned patents comprise of certain specific disintegrants, namely, a physiologically-acceptable edible acid and a mineral salt which releases a physiologically-acceptable gas upon ingestion, preferably carbon dioxide, e.g., a mineral carbonate or bicarbonate. These formulations also contain a soluble sugar, which greatly enhances the controllable disintegration of the unit dosage formulation upon ingestion in addition to providing a more generally acceptable flavor.


Accordingly, none of the oral sustained release drug delivery systems described above is completely satisfactory.
Our developed formulations have many advantages over existing formulations. Psyllium husk forms strong gel at concentrations used in the developed formulations. According to the present invention, the pharmaceutical composition contains a swelling agent that is capable of swelling to greater than its original volume and preferably to at least twice its original volume when coming into contact with a aqueous fluid, such as gastrointestinal fluid. In presence of such swelling agents, psyllium husk still maintains integrity of the matrix system. Psyllium husk forms very thick gel layer around swelling agents. In order to maintain the drug release from the matrix based formulations, we incorporated channeling agents such as cyclodextrins, eudragit E-100 that forms channels within the gel layer to obtain desired drug release profile. When psyllium husk is used in combination with carbopol 971P, it forms the matrix with strong dimensional stability as compared to the alone carbopol 971P matrix systems.
OBJECTS
The main object of the present invention is to develop a process for manufacture of an oral sustained release tablet dosage form with drug in a floating, swellable and bioadhesive carrier composition.
Another object of the present invention is to develop a suitable carrier composition that is floating, swellable and bioadhesive and sustained release tablet dosage form.


Another objective of this invention is to develop a process for manufacture of such a carrier composition, particularly for drugs that have an absorption window in the specific regions of stomach or upper parts of the small intestine. That is to develop a carrier system, which will remain in the stomach or upper part of small intestine.
Another object of the present invention is to develop a suitable carrier composition that provides swellable and / or bioadhesive matrix system useful for the sustained delivery of the drug preferably once daily formulations.


SUMMARY OF THE INVENTION
The present invention provides a process for the manufacturing of an oral sustained release tablet dosage form having one or more drugs or their pharmaceutically acceptable salts in a floating, swellable and bioadhesive carrier composition, comprising,
a. a powder of a drug or a drug powder composition comprising one or
more drugs or their pharmaceutically acceptable salts compatible with
each other, which are mainly used for sustained release formulations
preferably, once daily formulation
b. a carrier composition comprising,
i. gel forming and bioadhesive fiber 0.2-50%
ii. a swelling agents 0.5-40%
iii. one or more of hydrophilic water soluble polymers 5-20 %
v. gas generating agent 1-20 %
vi. excipients 1-5%
all percentages are by weight of the tablet composition;
Sieving and blending of all the ingredients of the tablet composition together that is followed by granulation using polyvinyl pyrrolidone (5% solution in isopropyl alcohol). Granules were compressed into a tablet after lubrication.
The present invention provides a process for the manufacturing of an oral sustained release tablet dosage form having one or more drugs or their

pharmaceutically acceptable salts in a floating, swellable and bioadhesive carrier composition, comprising,
a. a powder of a drug or a drug powder composition comprising one or more drugs or their pharmaceutically acceptable salts compatible with each other, which are mainly used for sustained release formulations preferably, once daily formulation and b. a carrier composition comprising,
i. gel forming and bioadhesive fiber 0.2-50%;
ii. a swelling agents 0.5-40%;
Hi. Channeling agents 0.5- 30%;
iv. One or more of hydrophilic water
soluble polymers 5-20 %;
v. gas generating agent 1-20 % ;
vi. excipients 1-5%
all percentages are by weight of the tablet composition;
Sieving and blending of all the ingredients of the tablet composition together that is followed by granulation using polyvinyl pyrrolidone (5% solution in isopropyl alcohol). Granules were compressed into a tablet after lubrication.
This system results in release of the drug into the more absorptive regions of the gastrointestinal tract i.e., into the stomach and the small intestine rather than into the large intestine where drug absorption is poor or erratic. Thus,


one may expect that if the drug is released at a constant and controlled rate,
it will also be absorbed at a more or less constant rate.
This is achieved by adjusting the time period of release for the drug so that it
is about the same as or less than the retention time of the tablets at the site of
absorption. This adjustment is possible with the adjustment of the
composition. Thus, the system is not transported past the "absorption
window" prior to releasing the entire drug, and maximum bioavailability is
attained.
DETAILED DESCRIPTION OF THE INVENTION
In order to get the desired system, at first incorporation of various polymers such as hydroxypropyl methyl cellulose, methyl cellulose and the like and their various combinations in a tablet were tried. Similarly, incorporation of different swellable and bioadhesive polymers such as guar gum, chitosan, pectin and the like in a tablet were tried. After extensive experimentation, trying many combinations of excipients this novel composition, that was closest to the objects set above was achieved. A pharmaceutical composition having such a combination of ingredients has not been disclosed earlier.
According to the present invention, when one or more drugs, gel forming and bioadhesive agent, swelling agents, hydrophilic water soluble polymers, gas generating agent, and excipients are compressed to form a tablet, and the tablet is administered orally, the system floats and delivers drug in sustained manner for a prolonged period of time. The improved sustained drug delivery system avoids dose dumping and results in the most therapeutic administration of a particular drug to a person with a particular ailment.

In the present invention, when the tablet comes into the contact with water, swellable polymers swell and form the hydrated matrix surrounded by gel layer. The gel forming fiber controls the swelling of the matrix, which acts as a drug release-controlling agent.
The characteristics of the hydrated gel matrix can be modified by altering the ratios and amounts of the swelling, bioadhesive and the water-soluble hydrophilic agent without loss of physical integrity of the hydrated gel system. The composition can thus be designed to obtain the optimal rate of release of the drug. Gel forming fibers control the swelling properties of the swellable polymer.
The presence of water-soluble polymer within the matrix can affect the diffusion path length of the drug and thus exerts a release-controlling effect.
The presence of swellable polymers such as cross carmellose sodium, cross
povidone, sodium starch glycolate and its expanding pressure affects the
influx of the acidic gastric fluid through the pores of the matrix and thus
exerts a release-controlling effect.
The present system advantageously contains the channeling agents such as
eudrgits and cyclodextrins which promote the drug release from thick
hydrated matrix formed by psyllium husk.
The various components of this system are as follows,
Drugs
The drugs used in the present invention are mainly those used for sustained release formulations preferably, once daily formulation and chosen from one or more of drugs like antibacterial/anti-infective agents and antibiotics, such


as ofloxacin, ciprofloxacin, cefuroxime axetil, cefatrizine, cefpodoxime proxetil, clarithromycin, loracarbef, azithromycin, cefixime, cefadroxil, amoxycillin, and the like; antivirals, such as acyclovir; cardiovascular agents, such as diltiazem, captopril, and the like; lipid lowering agents, such as simvastatin, lovastatin and the like; non-steroidal anti-inflammatory agents, such as etodolac, ketorolac, nimesulide, ibuprofen, ketoprofen and the like; anti-ulcer agents, such as ranitidine, famotidine, and the like; drugs for respiratory diseases, such as fexofenadine, pseudoephedrine, phenylpropanolamine, dextromethorphan, chlorphenirarnine, and the like; dopaminergic agents, such as bromocriptine; immunosuppressants, such as cyclosporin; skeletal muscle relaxants, such as baclofen; anti-gout agents, such as allopurinol; and the like.
The process of the present invention is particularly useful for orally administering the group of drugs having an absorption window in the specific regions of stomach or upper parts of the small intestine, in pharmaceutically effective amount.
The process of the present invention is more particularly useful for the group of drugs chosen from one or more of drugs like Ofloxacin; Acyclovir; Cefixime, and cephadroxil The drugs or combinations of the compatible drugs, used in this tablet form of the present invention are in pharmaceutically effective amounts.
Gel forming and bioadhesive fibers
In this invention, gel forming and adhesive fiber is psyllium husk. It is the upper coating of Plantago Ovata (Ispagul) which is highly purified by sieving and winnowing. Large quantity of mucilage is present in the husk.


Husk swells in to a jelly like mass with cold water. Mucilage has been found to be unaffected by the digestive enzymes and bacteria. It is colloidal in nature. It is mainly composed of xylose, arabinoise and galacturonic acid. Rhamnose and galactose have also been reported. Two polysachharide fractions have been separated from the mucilage. One fraction equivalent weight is 700 is soluble in cold water and on hydrolysis yields d-xylose (46%) an aldobiouronic acid(40%), 1-arabinose (7%) and insoluble residue (2%). The other fraction equivalent weight 4000 is soluble in hot water forming a highly viscous solution which sets to a gel on cooling and yields on hydrolysis d-xylose (80%), 1-arabinose (14%), an aldobiouronic acid (0.3%) and traces of d-galacose.
Swelling agents
According to the present invention, the pharmaceutical composition contains a swelling agent, which is capable of swelling to a greater than its original volume and preferably to at least twice its original volume when coming into contact with a aqueous fluid, such as gastrointestinal fluid. Swelling agent is chosen from a group of a superdisintegrants such as cross povidone, cross carmellose sodium, sodium starch glycolate and the like. The swelling agent, which normally swells to several times its original volume in water, exhibits a controlled swelling in the presence of gel forming fibers.
Hydrophilic water-soluble polymer
The tablet of the present invention contains a hydrophilic water-soluble polymer. Hydrophilic polymers is selected from the group consisting of a cellulose ethers, acrylic polymers, natural gums, and mixture thereof. The cellulose ether is selected from the group consisting of hydroxypropyl


cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, and mixtures thereof. The acrylic polymer is selected from the group consisting of methaacrylate, polyacrylates copolymers, and mixture thereof. The natural gum is selected from the group consisting of xanthan gum, karaya gum, locust bean gum, guar gum gellan gum, gum Arabic, tragacanth, carrageenan, pectin, agar, alginic acid, sodium alginate and mixture thereof.
Gas generating agents
Gas generating agents are carbonates, such as calcium carbonate or sodium glycine carbonate, bicarbonates such as sodium hydrogen carbonate or potassium hydrogen carbonate. When the formulation comes in contact with gastric fluid, the channeling agent forms channels through which gastric acid penetrate into the formulation and react with these agents to evolve carbon dioxide gas.


Channeling agents
Channeling agents used in the present invention are eudragits and cyclodextrins. Eudragit E-100 dissolves rapidly in gastric fluid forming channels within the thick matrix formed by psyllium husk and promotes the drug release. Similarly cyclodextrins dissolve rapidly in gastric fluid and promote the drug release.
EXCIPIENTS
The tablet of the present invention also contains other conventional pharmaceutical excipients, for example, water insoluble diluents such as starch, microcrystalline cellulose, powdered cellulose, and the like; or lubricants such as talc, stearic acid or its salt, magnesium stearate, and the binder such as polyvinyl pyrrolidone and the like. Lubricants are typically added to avoid the material(s) being tabletted from sticking to the punches. Commonly used lubricants include magnesium stearate and calcium stearate. Such lubricants are commonly included in the final tabletted product. This is important when sticky materials like gum are used.
Further coating of tablets is also useful for keeping the tablets in a pack in a free flowing condition.
Since most drugs cannot form tablets by themselves when compressed dry in a tablet making press, methods of tablet formulation have been developed in order to impart the desirable characteristics to the material(s), which is to be compressed into a solid dosage form. Typically, the material to be compressed into a solid dosage form includes one or more excipients, which impart the free flowing, lubrication, and cohesive properties to the drug(s) which is being formulated into a dosage form.

In addition to lubricants, solid dosage forms often contain diluents. Diluents
are frequently added in order to increase the bulk weight of the material to
be tabletted in order to make the tablet a practical size for compression. This
is often necessary where the dose of the drug is relatively small.
Another commonly used class of excipients in solid dosage forms is binders.
Binders are agents that impart cohesive qualities to the powdered
material(s).
Thus all the carrier materials are pharmaceutically accepted excipients. The
carrier materials used in this invention are of the nature of excipients and / or
diluents.
EXAMPLES
The invention will now be illustrated with the help of examples. The
examples are by the way of illustration only and in no way restrict the scope
of the invention.
Ofloxacin, acyclovir, cefixime and cephadroxil was obtained as gift samples from Macleoids Pharmaceuticals, India. |3- cyclodextrin was obtained from S.A. chemicals, India. Psyllium husk is the upper coating of Plantago Ovata (Ispagul) which is highly purified by sieving and winnowing.. Eudragit E-100 was obtained from Rohm pharma, Germany. All other chemicals are of analytical grade.
Ofloxacin, crosslinked polyvinylpyrrolidone, sodium bicarbonate, hydroxy propyl methyl cellulose were passed through a sieve (British Standard Sieve (BSS) No. 40) and mixed thoroughly. Psyllium husk was passed through a


Sieve No.80. Tablets were made by wet granulation process with 5% polyvinyl pyrrolidone K-30 in isopropyl alcohol.
The tablets were tested for dissolution in pH 1.2 buffer using USP Apparatus I with basket speed at 100 rpm. The drug release was estimated by UV spectrophotometry.
Buoyancy Test: The buoyancy lag time was determined in the USP 23 dissolution apparatus II in an acid environment as is outlined in the drug release section. The time interval between the introduction of the tablet into the dissolution medium and its buoyancy to the top of dissolution medium was taken as a buoyancy lag time.
% w/w
47.01
11.75
23.50
4.7
8.23
2.35
1.0
1.5
Examples 1
Ingredients
Ofloxacin
Psyllium husk
Crosslinked polyvinyl pyrrolidone
Hydroxypropyl methyl cellulose
Sodium bicarbonate
Polyvinyl pyrrolidone K-30
Magnesium Stearate
Talc

In vitro release:
Time (Hrs) % Cumulative release
1 10.80
2 15.82
4 21.85
6 24.06
8 31.00
Examples 2
Ingredients % w/w
Ofloxacin 41.96
Psyllium husk 10.49
Crosslinked polyvinyl pyrrolidone 20.98
P-cyclodextrin 10.49
Hydroxypropyl methyl cellulose 4.19
Sodium bicarbonate 7.34
Polyvinyl pyrrolidone K-30 2.09
Magnesium Stearate 1.0
Talc 1.5
In vitro release:
Time (Hrs) % Cumulative release
1 32.46
2 42.52
4 55.78
6 62.52
8 72.46


Examples 7
Ingredients
Ofloxacin
Psyllium husk
Hydroxypropyl methyl cellulose
Sodium bicarbonate
Carbopol 971P
Polyvinyl pyrrolidone K-30
Magnesium Stearate
Talc

%w/w
54.96
13.74
5.50
10.99
8.24
4.12
0.97
1.46



In vitro release:
Time (Hrs)
1
2
4
6
8

% Cumulative release 12.66 18.24
31.55 39.57 48.55



Examples 8
Ingredients
Cefixime
Psyllium husk
Crosslinked polyvinyl pyrrolidone
Hydroxypropyl methyl cellulose
Sodium bicarbonate
Polyvinyl pyrrolidone K-30

%w/w
34.99
15.64
25.02
9.38
9.38
3.12



Magnesium Stearate Talc

0.97 1.46



In vitro release:
Time (Hrs)
1
2
4
6
8

% Cumulative release 12.40 21.41 26.60 29.14 32.38



Examples 9
Ingredients
Cefixime
Psyllium husk
Crosslinked polyvinyl pyrroHdone
Euragit E-100
Hydroxypropyl methyl cellulose
Sodium bicarbonate
Polyvinyl pyrrolidone K-30
Magnesium Stearate
Talc

%w/w
32.39
14.48
23.16
7.24
8.68
8.68
2.89
0.974
1.46



In vitro release: Time (Hrs) 1
2

% Cumulative release 38.89 51.67

4 6 8

59.61 63.14 68.96



Examples 10
Ingredients
Cephadroxil monohydrate
Psyllium husk
Crosslinked polyvinyl pyrrolidone
Hydroxypropyl methyl cellulose
Sodium bicarbonate
Polyvinyl pyrrolidone K-30
Magnesium Stearate
Talc

% w/w
71.62
6.82
5.11
5.80
6.14
2.04
0.975
1.45



In vitro release:
Time (Hrs)
1
2
4
6
8

% Cumulative release 15.24 21.49 28.49 36.92 45.96



Examples 11
Ingredients
Cephadroxil monohydrate
Psyllium husk

%w/w
70.15
6.68




Crosslinked polyvinyl pyrrolidone
Hydroxypropyl methyl cellulose
Sodium bicarbonate
(3-cyclodextrin
Polyvinyl pyrrolidone K-30
Magnesium Stearate
Talc

5.01 5.68 6.01
3.34 2.04 0.975 1.46



In vitro release:
Time (Hrs)
1
2
4
6
8

% Cumulative release 17.59 27.13 41.96 54.76 75.96



Examples 12
Ingredients
Acyclovir
Psyllium husk
Crosslinked polyvinyl pyrrolidone
Hydroxypropyl methyl cellulose
Sodium bicarbonate
Polyvinyl pyrrolidone K-30
Magnesium Stearate
Talc

% w/w
55.86
16.57
8.37
4.88
8.37
3.49
0.89
1.34



In vitro release:
Time (Hrs) % Cumulative release
1 10.24
2 16.20
4 25.53
6 32.76
8 43.70
Examples 13
Ingredients % w/w
Acyclovir 51.44
Psyllium husk 15.43
Crosslinked polyvinyl pyrrolidone 7.71
Hydroxypropyl methyl cellulose 4.50
Sodium bicarbonate 7.71
╬▓-cyclodextrin 7.71
Polyvinyl pyrrolidone K-30 3.21
Magnesium Stearate 0.90
Talc 1.35
In vitro release:
Time (Hrs) % Cumulative release
1 18.54
2 23.76
4 31.24
6 40.30
8 60.17

Examples 14
Ingredients
Acyclovir
Psyllium husk
Crosslinked polyvinyl pyrrolidone
Hydroxypropyl methyl cellulose
Sodium bicarbonate
Eudragit E-100
Polyvinyl pyrrolidone K-30
Magnesium Stearate
Talc

% w/w
53.90
16.17
8.08
4.71
8.08
336
3.36
0.89
1.34



In vitro release:
Time (Hrs)
1
2
4
6
8

% Cumulative release 24.46 31.79 39.91 50.81 65.09

General information about dissolution profiles:
All the above formulations were tested for the buoyancy test. In all above-mentioned formulations, buoyancy lag time was found to be less than 60 second. As illustrated in examples 1, 2 and 3, as the concentration of (3-cyclodextrin increases, burst release of ofloxacin in first two hours increases,





which in turn increases total drug release. For example, in example 1, total drug release after eight hours in acidic medium is 31.00 % whereas it is 52.44 % in example 3 and the release increases to 72.46 % in example 2.
As illustrated in examples 1 and 5, eudragit E-100 increases the burst release of ofloxacin in first two hours hence increases the total drug release in acidic medium as compared to the formulation which does not contain eudragit E-100.
Eudragit El00 dissolves rapidly in gastric fluid forming channels within the thick matrix formed by psyllium husk and promotes the drug release. Similarly beta-cyclodextrin dissolves rapidly in gastric fluid and promotes the drug release
As illustrated in examples 6 and 7, when psyllium husk is used in combination with carbopol 971P, it forms the matrix with strong dimensional stability as compared to the alone carbopol 971P matrix systems.
ADVANTAGES OF THE INVENTION
The product of this invention provides increased gastric residence and thereby a longer period of residence of the drug delivery system in the gastrointestinal tract compared to conventional sustained release dosage forms.
The product of this invention provides swellable matrix system, which is
useful for the sustained deHvery of the drug preferably once daily
formulations.
It provides bioadhesive matrix system, which is useful for the sustained
deHvery of the drug preferably once daily formulations.


It delivers the drug at a controlled rate such that the drug is delivered over a
period of time, which is the same as or less than the period of residence of
the delivery system in the absorptive regions of the gastrointestinal tract.
It provides, as compared to other oral sustained drug delivery systems,
increased absorption of a drug that is absorbed largely from the upper parts
of the gastrointestinal tract.
It provides a pharmaceutical composition constituting an oral sustained drug
delivery system that maintains its physical integrity, i.e., remains intact or
substantially gains a monolithic form when contacted with an aqueous
medium.
The drug activity is not altered by the carrier system that is used in the
present invention.

I CLAIM
1. A process for the manufacturing of floating, swellable and bioadhesive
sustained release oral dosage form preferably once daily for oral
administration in humans for the controlled release of drugs comprising the
steps of:
(i). mixing of all the ingredients by conventional process,
(ii). granulating by conventional process and
(iii). compressing into dosages
having pharmaceutically effective amount of drugs such as ofloxacin or its
pharmaceutically acceptable salts and sustained release composition
comprising;
(a). 0.2 to 50% gel forming and bioadhesive fiber such as psyllium husk,
(b). 0.5 to 40% swelling agent such as crosslinked polyvinyl pyrrolidone
which is superdisintegrant,
(c). 0.5 to 25% channeling agent such as cyclodextrin, p-cyclodextrin or
eudragit E-100,
(d). 0.5 to 30% hydrophilic polymer such as hydroxypropyl methyl
cellulose,
(e). 1 to 25% gas generating agent such as sodium bicarbonate,
(f). 1 to 10% polyvinyl pyrrolidone,
(g). 1 to 5% excipients and
(h). optionally 2 to 25% carbopol 97IP.
2. A process for the manufacturing of floating, swellable and bioadhesive
sustained release oral dosage form preferably once daily for oral


administration in humans for the controlled release of drugs comprising the steps of:
(i). mixing of all the ingredients by conventional process, (ii). Granulating by conventional process and (iii). compressing into dosages
having pharmaceutically effective amount of drugs such as ofloxacin or its pharmaceutically acceptable salts and sustained release composition comprising;
(a). preferably 2 to 15% gel forming and bioadhesive fiber such as psyllium husk,
(b). preferably 10 to 25% swelling agent such as crosslinked polyvinyl pyrrolidone which is superdisintegrant,
(c). preferably 1 to 15% channeling agent such as cyclodextrin, [3-cyclodextrin or eudragit E-100,
(d). preferably 0.5 to 10% hydrophilic polymer such as hydroxypropyl methyl cellulose,
(e). preferably 1 to 10% gas generating agent such as sodium bicarbonate, (f). 1 to 5% polyvinyl pyrrolidone, (g). 1 to 5% excipients and (h). optionally 5 to 20% carbopol 971P.
3. A process for the manufacturing of floating, swellable and bioadhesive sustained release oral dosage form as claimed in claim 1-2 wherein, said gel forming and bioadhesive fiber is psyllium husk.
4. A process for the manufacturing of floating, swellable and bioadhesive sustained release oral dosage form as claimed in claim 1-2 wherein, swelling


agent is selected from a group of superdisintegrants such as crosslinked polyvinyl pyrrolidone, crosscarmellose sodium, sodium starch glycolate, gellan gum and xanthan SM.
5. A process for the manufacturing of floating, swellable and bioadhesive sustained release oral dosage form as claimed in claims 1-2 wherein, hydrophilic polymer is group consisting of a cellulose ethers, acrylic polymers, natural gums.
6. A process for the manufacturing of floating, swellable and bioadhesive sustained release oral dosage form as claimed in claims 1-2 wherein, gas generating agents are carbonates, such as calcium carbonate or sodium glycine carbonate and bicarbonates.
7. A process for the manufacturing of floating, swellable and bioadhesive sustained release oral dosage form as claimed in claim 1-2 wherein, channeling agent is cyclodextrins such as ╬▓-cyclodextrin or eudragit E-100.
8. A process for the manufacturing of floating, swellable and bioadhesive sustained release oral dosage form as claimed in claim 5 wherein, the cellulose ether is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxy cellulose.
9. A process for the manufacturing of floating, swellable and bioadhesive sustained release oral dosage form as claimed in claim 5 wherein, the acrylic


polymer is selected from the group consisting of methacrylate, polyacrylates copolymers.
10. A process for the manufacturing of floating, swellable and bioadhesive sustained release oral dosage form as claimed in claim 5 wherein, the natural gum is selected from the group consisting of xanthan gum, karaya gum, locust bean gum, guar gum, gellan gum, gum Arabic, tragacanth, carrageenan, pectin, agar, alginic acid, sodium alginate.
11. A process for the manufacturing of floating, swellable and bioadhesive sustained release oral dosage form as claimed in claims 1-2 wherein, drugs are chosen for sustained release preferably, once daily formulation like antibacterial/ anti-infective agents, such as ofloxacin, ciprofloxacin, cefuroxime axetil, ceftrizine, cefodoxime proxetil, clarithromycin, loracarbef, azithromycin, cefixime, cefadroxil, amoxycillin; antivirals, such as acyclovir; cardiovascular agents, such as dilteiazem, captopril; lipid lowering agents, such as simvastatin, lovastatin; non-steroidal anti┬Činflammatory agents, such as etodolac, ketorolac, nimesulide, ibuprofen, ketoprofen; anti-ulcer agents, such as ranitidine, famotidine; drugs for respiratory diseases, such as fexofenadine, pseudoephedrine, phenylpropanolamine, dexomethorphan, cholrpheniramine; dopaminergic agents, such as bromocriptine; immunosuppressants, such as cyclosporin; skeletal muscle relaxants, such as baclofen; anti-gout agents, such as allopurinol.


Documents:

769-mum-2002-cancelled pages(31-03-2004).pdf

769-mum-2002-claims(granted)-(31-03-2004).doc

769-mum-2002-claims(granted)-(31-03-2004).pdf

769-mum-2002-correspondence(26-05-2002).pdf

769-mum-2002-correspondence(ipo)-(21-07-2004).pdf

769-mum-2002-form 1(26-08-2002).pdf

769-mum-2002-form 19(08-08-2003).pdf

769-mum-2002-form 2(granted)-(31-03-2004).doc

769-mum-2002-form 2(granted)-(31-03-2004).pdf

769-mum-2002-form 3(16-10-2003).pdf

769-mum-2002-form 3(26-08-2002).pdf


Patent Number 205078
Indian Patent Application Number 769/MUM/2002
PG Journal Number 42/2008
Publication Date 17-Oct-2008
Grant Date 14-Mar-2007
Date of Filing 26-Aug-2002
Name of Patentee VAVIA PRADEEP RATILAL
Applicant Address MUMBAI UNIVERSITY INSTITUTE OF CHEMICAL TECHNOLOGY, N.P. MARG, MATUNGA, MUMBAI,
Inventors:
# Inventor's Name Inventor's Address
1 VAVIA PRADEEP RATILAL MUMBAI UNIVERSITY INSTITUTE OF CHEMICAL TECHNOLOGY, N.P. MARG, MATUNGA, MUMBAI - 400 019,
2 CHAVAN PATIL MAHESH DATTATRAY MUMBAI UNIVERSITY INSTITUTE OF CHEMICAL TECHNOLOGY, N.P. MARG, MATUNGA, MUMBAI-400019,
3 CHAUDHARI SACHIN VASANT MUMBAI UNIVERSITY INSTITUTE OF CHEMICAL TECHNOLOGY, N.P. MARG, MATUNGA, MUMBAI-400019,
4 JAIN PARAS RAMESHLAL MUMBAI UNIVERSITY INSTITUTE OF CHEMICAL TECHNOLOGY, N.P. MARG, MATUNGA, MUMBAI-400019,
PCT International Classification Number A 61 K 009/16
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA