FORM -2
THE PATENTS ACT, 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(See Section 10)
1. TITLE OF THE INVENSION
NOVEL ORAL CONTROLLED RELEASE DELIVERY SYSTEM
2. BLUE CROSS LABORATORIES LTD.of A-12, AMBAD INDUSTRIAL AREA,, NASIK-422 010, STATE OF MAHARASHTRA, INDIA, an Indian Company.
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

NOVEL ORAL CONTROLLED RELEASE DRUG DELIVERY
SYSTEM
FIELD OF INVENTION
The present invention relates to a novel oral controlled release formulation or composition in the form of tablet single or multi-layered, capsule, pellets, manufactured using a gel forming husk powder separated from seeds of Lepidium sativum, as primary release controlling agent, a drug or therapeutic agent, pharmaceutically accepted excipients like diluents, glidants, lubricants, binders etc. and optionally one or more cross-linking enhancer.
BACKGROUND OF INVENTION
The convenience of administering a single dose of a medication, which releases active ingredient in a controlled manner over an extended period of time, as opposed to the administration of a number of single doses at regular intervals, has long been recognized in the pharmaceutical arts. The advantage to the patient and clinician in having consistent and uniform blood levels of medication over an extended period of time are likewise recognized. The advantages of a variety of controlled release dosage forms are well known. Among the most important advantages are : (1) increased contact time for the drug to allow for local activity in the stomach, intestine or other locus of activity, (2) increased or more efficient absorption for drugs which have specific absorption sites; (3) the ability to reduce the number of dosages per period of time. (4) Employment of lower quantity of drug; (5) minimization or elimination of local and / or systemic side effects; (6) minimization of drug accumulation associated with chronic dosing; (7) improved efficiency and safety of treatment; (8) reduced fluctuation of drug level; and (9) better patient compliance with overall disease management.
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The patent and scientific literature is replete with various sustained release (SR) methods, release controlling agents and formulations. For example, it is known to fill capsules with solids, liquids, suspension or gel containing a therapeutic agent and polymer in capsules from which drug is slowly released by diffusion through the capsule walls. Heterogeneous matrices, for example, compressed tablets; control the release of their therapeutic agents either by diffusion, erosion of the matrix or a combination of both. Other SR systems focus on the fabrication of laminates of polymeric material and therapeutic agent which are then formed into a sandwich, relying on diffusion or erosion to control release of the therapeutic agent. Liquid- encapsulated in a viscous syrup-like solution of polymer, have also been known to be useful; in controlling release of the therapeutic agent. Additionally, it is generally known that heterogeneous dispersions or solution of therapeutic agents in water-swellable hydrogel matrices are useful in controlling the release of the agent by slow surface-to-center swelling of the matrix and subsequent diffusion of the active agent from the water-swollen part of the matrix.
During dissolution of a controlled release matrix tablet, the dosage form generally remains as a non-disintegrating, slowly eroding entity from which the therapeutic agent leaches out, through diffusion controlled process. Conventional SR formulations are generally designed to release their actives over an extended period of time, usually 8-24 hours. Conventional SR formulations use waxes or hydrophilic gums as the primary drug carriers to prolong the release of the active ingredients. In conventional wax matrix tablet formulations, the drug is dispersed in the wax matrix in the molten state. Conventional waxes and waxy materials used in pharmaceutical formulations are camauba wax, spermaceti wax, candellila wax, cocoa butter, cetosteryl alcohol, beeswax, partially hydrogenated vegetable oils, ceresin, paraffin, myristyl alcohol, stearyl alcohol, cetylalcohol and stearic
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acid. They are generally used in amounts of about 10 to about 50 % by weight of the total formulation.
Hydrophilic gums have also been known to be reasonably effective as SR carriers for both high-dose and low-dose drugs. Typical hydrophilic gums used as SR carrier materials are acacia, gelatin, tragacanth, veegum, xanthan gum, carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and hydroxyethyl cellulose (HEC). Generally these materials are present in amounts of about 10 to 50 % by weight of the final formulation.
U S Patent No. 4,994,276; 5,128,143; 5,135,757 and 6,093,980 described controlled release excipients, which are comprised of synergistic heterodisperse polysaccharides. They are useful as release retardants in the preparation of oral solid dosage forms using either direct compression or conventional wet granulation, or combination of the two. The release of medicament from the formulation therein proceeds according to zero-order or first order mechanisms. The sustained release excipients disclosed in U S Patent No. 4,994,276; 5,128,143 and 5,135,757 are commercially available under trade name TIMERx..TM. from Edward Mendell Co., Inc., Patterson, N. Y.
U S Patent No. 6,093,980 describes sustained release formulation for use in oral solid dosage forms which includes about 10 to 40 percent or more by weight galactomannan gum; from about 1 to about 20 percent by weight of an ionizable gel strength enhancing agent and an inert pharmaceutical filler.
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U S Patent No. 6,136,343 describes the heterodisperse hydrogel system for insoluble drugs. This SR formulation includes Xanthan and Locust Bean Gum in ratio about 1:3 to about 3:1 as gelling agent, an optional cationic cross-linking enhancer, an inert pharmaceutical diluent and medicament having moderate to poor solubility. Additionally this system also requires hydrophobic polymer coating on unit dosage form. It is well recognized by those skilled in the art that it may be difficult to obtain the desired rate of release for a drug using so many controlling ingredients and also system is restricted for poorly soluble drugs.
Gums and mucilage have different structure but are polysaccharides, containing several sugars with alternating monomer structures and may or may not contain uronic acids. There are many mucilage and gum containing seeds found in plants and cereal grains. Guar and Locust bean gums are galactomannans, whereas gum Arabic is an acidic polymer of galactose and rhamnose. Oat and barley contain gums, but are not practical for use in present application due to low percentage of active gum or weight volume. In present application 'Lepidium sativum seed husk' is principle gel forming agent.
A co pending Indian patent application No. 560/mum/200l by us on the method of manufacturing of husk from Lepidium sativum seeds describes in detail procedure of obtaining husk powder from seeds.
Lepidium sativum husk mainly consists of polysaccharides, which comes under the class of compounds called as "dietary fibers". The term "dietary fiber" is defined as remnants of plant cells resistant to hydrolysis by alimentary enzyme of man, the group of substances that remain in ileum but are partly hydrolysed by bacteria in colon (JAMA 262, No. 4, 542546 [Jul 28, 1989]). Gel forming dietary
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fibers includes mucilages, plant gums, pectins or pectin substances and lignin, all of which are endogenous compounds of plant materials, which are resistant to digestion by enzyme in stomach or intestine. Chemically nearly all of these plant materials are carbohydrates composed of repeating sugar (monosaccharides) units. Water-soluble fraction of these substance forms gels in stomach and intestinal tract in presence of biological fluid.
Lepidium sativum (Family: Cruciferae) popularly known as Garden Cress or Water Cress in English and haliv/ ahaliv / Chandrashoor in local languages in India, is a native plant of southwest Asia and spread many centuries ago to Western Europe. Xenophon (400 BC) {Neglected Crops: 1492 from a Different Perspective, 1994, J. E. Hernando Bermejo and J Leon (eds.) Plant Production and Protection Series No. 26 FAO, Rome, Italy, p-303-332} mentions that Persians used to eat this plant even before bread was known. Seeds of Cress plant have been found in the tombs of ancient Egyptian pharaohs. (From the web site www.ks.essortment. conVnaturalhomesere_rmss.html)
Garden Cress is a small, herbaceous glabrous, annual growing plant up to 50 cm. This plant is cultivated as salad plant throughout India. (The Wealth of India, A Dictionary of Indian Raw materials & Industrial Products, Raw Material, Vol- VI, Council of Scientific & Industrial Research, New Delhi, 1962, p- 70-73) From ancient times, garden cress seeds, leaves, roots and flowers are regularly used for treating various diseases or disorders. Leaves are gently stimulant and diuretic. Seeds are aperients, diuretic, alternative tonic, demulcent, aphrodisiac, carminative. (Indian Medicinal plants, Vol-III, Vaidyratnam P. S. Varier's Arya Vaidya Sala, Kattakal, Orient Longman Publication, 1995, p-313.) Mucilage of the seeds allays the irritation of mucous coat of intestine (The Wealth of India, A
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Dictionary of Indian Raw materials & Industrial Products, Raw Material. Vol- VI, Council of Scientific & Industrial Research, New Delhi, 1962, p- 70-73). Following preparations containing seeds of Lepidium sativum are described in traditional Indian as well as in International Literature.
Nadkarni et al (The Indian Materia Medica, Vol-II, p-736-738) described following household formulations containing Lepidium sativum seeds.
1) One part of seeds added to twenty parts of boiling water or ten parts of cold water, when consumed orally, is remedy for dysentery, diarrhea and skin diseases caused by impurity of blood.
2) Seeds are recommended for the dispersion of certain chronic enlargement of spleen.
3) Powder of Lepidium sativum seeds with sugar can also be used to cure diarrhea, indigestion and dysentery.
4) A preparation made of seeds, ghee and sugar in the form of "laddoos" is a common household remedy useful as a restorative in general weakness. Indians very commonly eat Lepidium sativum seeds in the form of laddoos. The laddoos are specifically given to lactating mothers in the postnatal period. (Sahastrabuddhe, M B., and N. N. De, Current Science, 12, 1943,, 1, p-23-24)
Bhavpraksh, (a standard reference book of Ayurveda) described emulsion made by soaking or boiling one part of Lepidium sativum seeds in eight part of water for relieving hiccups.
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Baisubramaniam et al (Ind. Jour. Med. Res., 50, 5, 1962, p-779-793.) from Nutrition Research Laboratory', Hyderabad also confirmed the use of Lepidium sativum seeds as a food item with a remark "seeds with 100% edible portion"
Thus there are quite a few references in ancient standard Indian medicinal books regarding safe consumption of seeds of Lepidium sativum. In fact ahaliv seeds are used as household food item.
Adam et al ("Effect of various levels of dietary Lepidium sativum in rats", Am. Jr. of Chinese Medi., 27 (3.4), p-397-405, 1999) performed a toxicity study on Lepidium sativum seeds using Wistar albino rats at 2 % (w/w) of the diet was found to be non-toxic, 10 %(w/w) of the diet was toxic but not fatal and 50 % (w/w) of the diet for 6 weeks was lethal and caused depression in growth rate and entero-hepato-nephrotoxicity.
Karnick et al (Pharmacopoeial Standards of Herbal plants, Vol-I, 1994, Sri Satguru Publ., Ind. Medical Sci, Ser. No. 36, p- 219-220) described pharmacology of ethanolic extract of seeds of Lepidium sativum. Ethanolic extract have anti¬spasmodic effects on isolated guinea-pig ileum with LD50 1000 mg/kg body weight of albino mice when given intraperitonally.
Patole et al ("Effect of mucilaginous seeds on in vitro rate of starch hydrolysis and blood glucose levels of NIDDM, subjects with special reference to Garden Cress Seeds", Jr. of Medi. and Aromatic Plant Sci., 20 (4), p-1005-1008, December, 1998) studied the antidiabetic activity of Lepidium sativum seeds on 11 NIDDM subjects as well as 14 normal healthy subjects by administering 15
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gm seeds per day. In the long term (21 days) treatment they found that seeds possess some hypoglycemic activity.
All the above information proves beyond doubt that Garden cress seeds are very safe with respect to human consumption.
Kulkarni et al ("Some Physicochemical Characteristics of Lepidium sativum (haliv) seeds", Die Nahrung, 37, (1993), 1, p-69-71) studied physical characteristics of Lepidium sativum seeds such as colour, length, shape, bulk density, weight and swelling Index and chemical characteristics such as proximate composition and carbohydrate profile. Water holding capacity of seeds was measured at room temperature, refrigeration and at 50°C. They have found high pentosan content (11%) and also high fiber values and concluded that Lepidium sativum seeds can be a non-conventional but promising source of dietary fiber and associated nutritional properties in addition to its high nutritional and caloric value.
The wealth of India gives detail composition of garden cress seeds as follows, (The Wealth of India, A Dictionary if Indian Raw materials & Industrial Products, Raw Material, Vol- VI, Council of Scientific & Industrial Research, New Delhi, 1962, p- 70-73) Moisture 5.69%, Protein 23.5%, fats 15.9%, ash 5.7%, Phosphorous (P205) 1.65%, Calcium 0.31% and sulphur 0.9 %. The seed contains an alkaloid (0.19 %), glucotropaeolin, sinapin (Choline ester of sinapic acid), sinapic acid (4-hydroxy, 3,5 dimethoxy cinnamic acid C11H12O5 M.P. 192°C), mucilaginous matter (5 %) and uric acid (0.108 g/kg). The mucilage consists of a mixture of cellulose (18.3 %) and uronic acid containing polysaccharides, acid
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hydrolysis of which yields L - arabinose, D-galactose, L-rhamnose, D-galactouronic acid and D-glucose.
Previously many scientists tried to use various dietary fibers as excipients for controlling release of drugs or therapeutic agent. Various unsuccessful attempts have been made to solve the problem of improper and incomplete dissolution of guar gum tablets. EPA 0080673 describes these problems in detail, and discloses the use of 5 to 30 % of highly dispersed silica gel in Guar gum containing tablet. Normally used tablet disintegrants or additives such as Polyvinylpyrrolidone sodium, carboxymethyl-starch, cornstarch, microcrystalline cellulose, and so on, do not lead to satisfactory results. Hard tablets are produced which do not swell properly and which form an impenetrable layer of gel around a powder core which may pass through the gastrointestinal tract undissolved and nearly intact.
U.S. Patent No. 5,445,826, U.S. Patent No. 5,292,518, U.S. Patent No. 5,096,714 describes the use of gums or psyllium husk in combination with mineral carbonates or bicarbonates, a physiologically acceptable acid may optionally be included in composition to give prolonged action. Here need of mineral salts or acid may give rise to formulation problems, stability problems of dosage forms. To avoid this there is a mention of coating of gums and active ingredients with sodium carboxymethyl cellulose followed by 2% dispersion of surelease. This further complicated the formulation (U.S. Patent no. 5,445,826)
It is apparent that the prior art has not provided any suitable, controlled release unit dose formulation for controlling the release of a therapeutic agent or drugs alone or in combination, which employs or embodies a gel forming dietary fiber as a primary release controlling agent. This may be because of the fact that the
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swelling, balling and a plug forming properties of previously known gel forming dietary fibers has heretofore been considered as insurmountable disadvantage.
This invention provides a novel oral drug delivery system employing "husk" powder separated from seeds of Lepidium sativum. This husk is rich in mucilage, which readily swells more than fifteen times its original volume in presence of water and biological fluids, forming a gel. This separated husk optionally in combination with cross-linking enhancer can deliver the therapeutic agent or drug throughout gastrointestinal tract independent of pH over an extended period of time.
From prior art, it is apparent that there are many polymers available for controlling the release of drug, but each one them have its own limitations like pH dependency, viscosity dependency, biocompatibility and etc. Hence there is a need to provide a natural material, which is a food item and is having, hence, there is a need to provide a natural material which is a food item and is having very unique properties like swellability, gellability in wide pH ranges. This attribute of the material qualifies it a versatile and useful controlled release agent.
OBJECTS OF THE INVENTION
It is an objective of the invention to provide novel and advantageous controlled release platform technology for unit dosage formulation and a method for controlling the release of a drug with varied physicochemical characteristics upon administration to a human being involving the employment of such improved and advantageous controlled release unit dosage formulation of the invention.
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Another objective of the invention is to provide such formulation and method which involves the employment of extended release unit dosage formulation consisting essentially of an effective dose of therapeutic agent or drug alone or in combination, a gel forming husk powder separated from Lepidium sativum seeds and optionally one or more cross-linking enhancers.
A further objective of invention is to provide above composition in the form of once or twice daily formulation just by changing the amount of gel forming compound and optionally one or more cross-linking enhancers.
A further objective of the invention is to provide controlled release oral drug delivery system encompassing all types of drugs or therapeutic agents like highly soluble, moderately soluble, insoluble, acidic and basic.
A further objective of present invention is to provide oral drug delivery system, which can control release of drugs having dosage ranging from 1 mg to 1200 mg.
A further objective of the present invention is to make controlled drug delivery systems in the form of single layered, multi-layered tablets, capsules or pellets of one drug substance or combination of more than on drug substances.
SUMMARY OF INVENTION
In accordance with the present invention a controlled release unit dosage formulation or composition is provided which controls the release of drug or therapeutic agent upon administration to human being. The formulation essentially consists of an effective dose of biologically absorbable drug or therapeutic agent, a novel gel forming dietary fiber, pharmaceutically acceptable
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excipients and optionally a cross-linking enhancer. The dietary fiber is husk powder separated from Lepidium sativum seeds. Cross-linking enhancer is selected from gums, such as, Carragennan gum, karaya gum, tragacanth gum, ghatti gum, glucomannan, guar gum, gum acacia, locust bean gum, xanthan gum, veegum, gellan gum and cellulose derivatives like methyl cellulose, hydroxy propyl methyl cellulose, hydroxy propyl cellulose, carboxymethyl cellulose, ethyl cellulose, hydroxy ethyl cellulose and its derivatives, pectins, lignin, chitins and its derivatives, acrylic acids and its derivatives, agar, gelatin, polyvinyl alcohol and carbopols or a combination of more than one thereof. The cross-linking enhancer may be present in the concentration about 1 to 20 % by weight of total formulation.
Further the unit dosage form may or may not contain water-soluble or water insoluble diluent. It may also contain binder known to those who are skilled in the art like starch, polyvinylpyrrolidone (PVP 90) or Hydroxypropyl methylccllulose, or hydroxypropyl cellulose as binder. For granulation of the blend non-aqueous vehicle were used. Further the unit dosage form optionally contains pharmaceutically acceptable excipients. The tablet may be coated with hydrophilic fast dissolving polymer for elegance and bitter taste masking purpose.
DETAILED DESCRIPTION OF THE INVENTION
According to present invention the oral controlled release unit dosage form, especially tablets single layered or multi-layered, capsules and pellets essentially consists of a drug or therapeutic agent, a novel gel forming compound, a husk powder separated from seeds of Lepidium sativum, pharmaceutically acceptable excipients and optionally one or more cross-linking enhancers. This combination produced a unique, controlled action and advantageous delivery system. Thus this
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system serve dual purpose, delivering the drug through gastrointestinal tract uniformly and thus improving its Bioavailability and at the same time this dietary fiber due to its swelling and gelling property could potentially loosely interact with the mucin in the gastrointestinal tract and thereby coat the inner lining of the tract and thus buffering the contact of drug with intestinal lining. The above hypothesis is included for discussion purpose only and is not intended to limit the scope of the present invention.
The controlled release delivery system comprises of following components:
A| Lepidium sativum husk powder
Lepidium sativum husk alone or in combination with cross-linking enhancer when formulated in the form of tablet single layered or multi-layered, capsule and pellets produce a hydrogel matrix. This is a three dimensional, water-swollen structure composed of mainly hydrophilic homopolymers or copolymers. They arc rendered insoluble due to the presence of chemical or physical cross-links. The physical cross-links can be entanglements, crystallites or weak van der Waals forces or Hydrogen bonds. The cross-links provide the network structure and physical integrity.
Cress seed husk powder in presence of biological fluid in gastrointestinal tract absorb water and swell. This swelling property of husk is mainly because of mucilaginous matter present in it. The mucilage consists of a mixture of cellulose (18.3 %) and uronic acid containing polysaccharides. This in presence of water, the polyuronide chains, containing ionisable carboxyl groups, become hydrated and swell and the cellulose micelles become dispersed. Thus gel consists of a network of hydrated cellulose micelles, interspersed with more heavily hydrated
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uronide chains. The extent of dispersion depends upon ultimately on the size of the cellulose micelle, the chain length and the proportion of hydrated polyuronides. Because of their high water content and rubbery nature, they resemble natural living tissue more than any other class of synthetic materials. Thus system is biocompatible, biodegradable and devoid of any unwanted characteristic side effects of synthetic polymers, which are traditionally used to modify drug release. Because of natural source of Lepidium sativum husk, presence in abundance, easy cultivation and amount required to extend the delivery of therapeutic agent is optimum; use of this dietary fiber is very cost effective.
In swelling controlled release systems, the drug is dispersed within a glassy polymer. Upon oral ingestion and contact with gastric fluid, the controlled release formulations prepared according to the present invention begin to swell and gel. As the penetrant enters the glassy polymer, the glass transition temperature of the polymer is lowered allowing for relaxations of the macromolecular chains. The drug is able to diffuse out of the swollen, rubbery area of the polymers. This type of system is characterized by two moving fronts: the front separating the swollen (rubbery) portion and the glassy regions, which moves with velocity, and the polymer-fluid interface. The rate of drug release is controlled by the velocity and position of the front dividing the glassy and rubbery portions of the polymer. Since the medicament is dispersed throughout the tablet (and consequently throughout the gel matrix), a constant amount of drug can be released per unit time in vivo by dispersion or erosion of the outer portions of the matrix. The chemistry of certain ingredients, which are the essential part of the present invention, such as Lepidium sativum husk is such that the excipients are considered to be self-buffering agents, which are substantially insensitive to the
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solubility of the medicament and likewise insensitive to the pH changes along the length of the gastrointestinal tract.
In a preferred embodiment of present invention the pharmaceutical composition comprised from about 10 to 70 % by weight of husk powder separated from Lepidium sativum seeds. In a preferred embodiment, pharmaceutical compositions comprised from about 10 to 60 % by weight of husk powder separated from Lepidium sativum seeds.
BJ Drug
According to present invention the pharmaceutical composition contains biologically absorbable drug or therapeutic agent in an amount from about 10 to 75 % by weight.
Illustrative examples of drugs that are suitable for the present invention are selected from the group consisting of analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agent, anti-asthma agent, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agent, anti-hypertensive agents, anti-malarials, anti¬migraine agent, anti-muscarinic agents, anti-neoplastic agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anti-tussives, bronchodilators, anxiolytic, sedatives, hypnotics, neuroleptics, beta -Blockers, cardiac inotropic agents, corticosteriods, diuretics, anti-parkinsonian agent, gastro-intestinal agents, histamine H, -receptor antagonists, keratolytics, lipid regulating agent, muscle relaxants, anti-anginal agents, nutritional agents, NSAID's, analgesics, stimulants, antibacterial / anti-infective agents and mixtures thereof.
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Therapeutic agent or drug suitable for present invention is selected from the goup consisting of, ciprofloxacin, ofloxacin, grepafloxacin, levofloxacin, lomefloxein, sparfloxacin, gatifloxacin, norfloxacin, alatrofloxacin, moxifloxacin, cefuroxne. cefadroxil, cefuroxime sodium, cefaclor, cefradine, cefatrizine, cefdinir, ceftrixone, ceftizoxime, cefoxitin sodium, cefotoxine, cefonicid, cefixime, cefepime hydrochloride, cefamandole naftate, cephalexin, cephapirin sodiurr. cefuroxime axetil, cefpodoxime, clarithromycin, streptozocin, polymixin B sulphate, azithromycin, roxithromycin, clindamycin, and its derivatives loracarbef, azithromycin, cefixime, cefadroxil, amoxycillin, ampicillin, cloxacillin, and the like; antivirals, such as acyclovir; ganciclovir, cidofovir cardiovascular agents, such as diltiazem, captopril, and the like; lipid lowering agents, such as simvastatin, pravestatin, lovastatin, atorvastatin and the like: jun-steroidal anti-inflammatory agents, such as diclofenac sodium, nimesulide, Celecoxib, rofecoxib, valdecoxib, etodolac, ketorolac, and the like; anti-ulcer agents, such as ranitidine, famotidine, Omeprazole and its derivatives and the like; drugs for respiratory diseases, such as agents, such as fexofenadine, pseudoephedrine, phenylpropanolamine, dextromethorphan, chlorpheniramine and the like; dopaminergic agents, such as bromocriptine; immunosuppressants, such as cyclosporin; skeletal muscle relaxants, such as baclofen; anti-gout agents, such as Allopurinol; anti-diabetic like metformin hydrochloride, acarbose, glipizide, proglitazone, pioglitazone, glimepiride, gliclazide and combination thereof, anti-aids agents like lamivudine, zidovudine, nivarapine and combination thereof, anti-tubercular agents like rifampicin, isoniazide, pyrazinamide, ethambutol, rifapentin, rifabutane and the like. The drug itself or its pharmaceutically acceptable salt or ester may be used in the present invention Moreover, combinations of drugs that are typically administered together may be
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I

included as the drug component of the pharmaceutical composition. The amount of drug to be used in the composition is that which is typically administered for a given period of time.
Further the active agent or their pharmaceutically acceptable hydrates; salts or esters may be present in an amount from 1 mg to 1200 mg per dosage form
C| Cross-linking enhancer
According to present invention the pharmaceutical composition contains gel forming husk separated from seeds of Lepidium sativum. Amount of compound used is depending on release profile required; solubility of therapeutic agent in gastrointestinal medium as for the matrix system solubility of therapeutic agents is major release controlling parameter. For moderately soluble therapeutic agent or drug Garden Cress husk alone can be used to formulate twice-daily preparation. To avoid initial bursting effect, the release retardation in the initial hours was done by stiffening the matrix preferably by adding one or more cross-linking enhancer.
Cross-linking enhancer is selected from gums, such as, Carragennan gum, karaya gum, tragacanth gum, ghatti gum, glucomannan, guar gum, gum acacia, locust bean gum, xanthan gum, veegum, gellan gum and cellulose derivatives like hydroxy propyl methyl cellulose, hydroxy propyl cellulose, carboxymethyl cellulose and its derivatives, pectins, lignin, chitins and its derivatives, acrylic acids and its derivatives, agar, gelatin, polyvinyl alcohol and carbopol or a combination of more than one thereof, can be used as cross-linking enhancer. The cross-linking enhancer, if present, in the concentration ranging from 3% to 10% by weight of the husk powder.
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To clearly evaluate the role of cross-linking enhancer, experiments were conducted using Diclofenac Sodium as a model drug and the cross-linking enhancer in the concentration of approx. 6.6% by weight of dosage form and produced the tablets which were subsequently studied for drug release and we have found that 100 % drug was released within 3 hours in 7.4 pH phosphate buffer. Whereas, when the same cross-linking enhancer (in the concentration of 3.8% of the weight of dosage form) along with cress husk powder controlled the release of Diclofenac Sodium up to 16 hours in 7.4 pH phosphate buffer. Thus cross-linking enhancer acts synergistically beyond proportion in controlling the release of the therapeutic agent. It was also playing a role in increasing the viscosity of system internally so that there was proper engulfment of the particles of drug or therapeutic agent particles inside the matrix releasing them in a controlled manner.
In a preferred embodiment of present invention the pharmaceutical composition comprises from about 1 to 10 %, preferably 3 to 10%, by weight of one or more cross-linking enhancer.
D] Pharmaceutical acceptable excipients
The pharmaceutical acceptable excipients is selected from one or more of water soluble or insoluble diluent. Preferably the water soluble and or insoluble diluents are present in an amount from about 10 to 40 % weight of total weight of composition.
Examples of water-soluble diluents that were used in present invention include but not limited to lactose, sucrose, mannitol and like. Examples of water-insoluble
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diluents that were used in present invention include but not limited to dibasic calcium phosphate, starch, microcrystalline cellulose etc.
Excipients may include pharmaceutical grade anti-adherent like colloidal silicon dioxide (aerosil 200) as a lubricant in matrix formulation. Magnesium stearate or stearic acid, talc and colloidal silicon dioxide may be used in an amount ranging from 0.2 % to 5.0 % by weight either alone or in combination. Other conventional pharmaceutical auxiliary components such as antioxidants may be used. The choice of auxiliary components and the amounts to be used is considered to be within the purview of one skilled in the art.
The tablets or pellets may be optionally film-coated with rapidly dissolving water-soluble film forming polymer like hydroxy propyl methylcellulose, acrylate, polyvinyl alcohol and many more. The tablet may be coated to weight build up of about 1 to 4 % by weight preferably from about 1 % to 2 % by weight
Preferably the coating composition contains colouring agent and an opacifier in order to improve appearance.
According to the present invention, excellent controlled release unit dosage formulations are provided, each consists essentially of selected biologically absorbable therapeutic agent or drug either alone or in combination, a novel gel forming compound separated from garden cress seeds and optionally cross-linking enhancer.
According to present invention the biological liquid such as stomach acid begins to penetrate into extended release unit dosage formulation rendering the gel
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forming compound absorb medium, swell and form a hydrogel. Cross-linking enhancer if present assists in rapidly forming porous, stiff gel like structure. Through this porous structure, therapeutic agent is released depending on amount of gel forming agent present. Because of moderately slow hydrating nature of mucilaginous compound, the loading dose of the drug can immediately be released to illicit initial biological response. This burst effect can be easily controlled by just altering quantity of husk. This formed hydrogel then considerably retard the release of remaining therapeutic agent or drug within the dosage form and releases it over a period of time depending upon the amount of gel forming compound present in the dosage form.
The uniqueness of this invention is that merely by altering the amount of husk in the dosage form one can modulate the release profile of any drug molecule mentioned herein irrespective of its physicochemical properties, which qualifies it as a platform technology.
DETAILED DESCRIPTION OF PROCEDURE OF MAKING UNIT DOSAGE FORM
According to the present invention, for making the composition, the biologically absorbable drug or therapeutic agent, gel forming husk powder separated from Lepidium sativum seeds, optionally a cross-linking enhancer and pharmaceutically acceptable diluents were first sifted through 250um sieve and then mixed together in octagonal blender. In non-aqueous vehicle preferably isopropyl alcohol, optionally binder polyvinylpyrrolidone or hydroxypropyl methylcellulose, or hydroxypropyl cellulose was dissolved under stirring. Isopropyl alcohol without binder can also be used. Granulation was carried out in
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planetary mixer or rapid mixer granulator. Granules were dried in fluidized bed dryer. Dried granules were sifted through 1 mm sieve (BSS 16#) to reduce particle size. Then blend was lubricated using the pharmaceutically acceptable lubricants, glidants, anti-adherants and then after mixing in octagonal blender was compressed into tablets.
The tablet may be optionally coated with rapidly dissolving water-soluble film forming polymer. The tablet may be coated to weight build up of about 1 to 4 % by weight preferably from about 1 % to 2 % by weight.
Preferably the coating composition contains colouring agent and an opacifier in order to improve appearance.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Following examples are given to illustrate the composition and method of present invention, but are not to be constructed as limiting.
Example 1:
Diclofenac Sodium is representing a basic molecule with moderate dose and moderate water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm2) according to following formulation.
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Ingredients mg/tab Percentage
Diclofenac Sodium 100.00 38.16
Garden Cress husk 120.00 45.80
Xanthan gum 12.00 4.58
Lactose 20.00 7.63
Magnesium stearate 3.00 1.14
Talc 4.00 1.52
Aerosil-200 3.00 1.14
Diclofenac Sodium, Garden Cress Husk, Xanthan gum and Lactose were sifted through 250µm (BSS 40 #) sieve and mixed well. This blend was granulated in planetary mixer using Isopropyl Alcohol. Granules were dried in Fluidized Bed Dryer (FBD) at 50°C. Granules were passed through 1 mm (BSS) sieve and lubricated with Aerosil 200, Magnesium Stearate and Talc and compressed the blend for preparing tablets.
Dissolution was performed as per USP XXIV in 1.0 liter 7.4 pH Phosphate Buffer (0.05M) 100 RPM, at 37°C using apparatus 1. Release profile was as follows:

Example 2:

TIME (HOUR) % DRUG DISSOLVED
1 10.13
2 15.79
4 25.95
8 42.21
12 54.99
16 67.29

Ingredients mg/tab Percentage
Diclofenac Sodium 100.0 46.29
Garden Cress husk 60.0 27.78
Xanthan gum 6.0 2.78
Lactose 40.0 18.52
Magnesium stearate 3.0 1.38
Talc 4.0 1.85
Aerosil-200 3.0 1.38
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Diclofenac Sodium, Garden Cress Husk, Xanthan gum and Lactose were sifted through 250µm (BSS 40 #) sieve and mixed well. This blend was granulated in planetary mixer using Isopropyl Alcohol. Granules were dried in Fluidized Bed Dryer (FBD) at 50°C. Granules were passed through 1 mm (BSS) sieve and lubricated with Aerosil 200, Magnesium Stearate and Talc and compressed the blend for preparing tablets.
Dissolution was performed as per USP XXIV in 1.0 liter 7.4 pH Phosphate Buffer (0.05M) 100 RPM, at 37°C using apparatus 1. Release profile was as follows:

TIME (HOUR) % DRUG DISSOLVED
1 14.04
2 22.42
4 37.31
8 60.86
12 78.39
16 93.31
Example 1 and 2 clearly reveals that merely by altering the proportion of polymers in the system and keeping all other parameters constant, there is substantial difference in release profile. This conclusively proves the theory that polymer system is versatile and simple. Example 3:

Ingredients mg/tab 100.0 Percentage
Diclofenac Sodium
40.8
Garden Cress husk 95.0 38.7
Xanthan gum 9.5 3.87
Lactose 30.5 12.4
Magnesium stearate 3.0 1.22
Talc 3.0 1.22
Aerosil-200 4.0 1.63

Diclofenac Sodium, Garden Cress Husk, Xanthan gum and Lactose were sifted through 250µm (BSS 40 #) sieve and mixed well. This blend was granulated in planetary mixer using Isopropyl Alcohol. Granules were dried in Fluidized Bed Dryer (FBD) at 50°C. Granules were passed through 1 mm (BSS) sieve and lubricated with Aerosil 200, Magnesium Stearate and Talc and compressed the blend for preparing tablets.
Dissolution was performed as per USP XXIV in 1.0 liter 7.4 pH Phosphate Buffer (0.05M) 100 RPM, at 37°C using apparatus 1. Release profile was as follows:

TIME (HOUR) % DRUG DISSOLVED
1 13.30
2 23.44
4 8 41.52 69.85
12 86.02
16 96.45
This formula best describes formulation for once daily administration of Diclofenac Sodium.
Example 4: Diclofenac Sodium formulation with Xanthan gum alone.
This is to demonstrate that cross-linking enhancer alone does not effectively control the release of drug in the said concentration.

Ingredients mg/tab Percentage
Diclofenac Sodium 100.0 66.67
Xanthan gum 9.5 6.33
Lactose 30.5 20.33
Magnesium stearate 3.0 2.0
Talc 3.0 2.0
Aerosil-200 4.0 2.67
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Diclofenac Sodium, Xanthan gum and Lactose were Sifted tiirough 250µm (BSS 40#) sieve and mixed well. This blend was granulated in planetary mixer using Isopropyl Alcohol. Granules were dried in tray dryer or Fluidized Bed Dryer (FBD) at 50°C. Granules were passed through 1 mm (BSS 16 #) sieve and lubricated with Aerosil 200, Magnesium Stearate and Talc and compressed the blend for preparing tablets.
Dissolution was performed as per USP XXIV in 1.0 liter 7.4 pH Phosphate Buffer (0.05M) 100 RPM, at 37°C using apparatus 1. Release profile was as follows:

TIME (HOUR) % DRUG DISSOLVED
1 30.24
2 87.26
3 98.47
Thus Xanthan gum in same proportion as in Example 1 alone could not control release of the drug for more than 3 hours.
Example 5:
Diclofenac Sodium formulation for twice daily administrstion.

Ingredients mg/tab Percentage
Diclofenac Sodium 100.0 48.78
Garden Cress husk 95.0 46.34
Magnesium stearate 3.0 1.46
Talc 3.0 1.46
Aerosil-200 4.0 1.95
Diclofenac Sodium, Garden Cress Husk, were sifted through 250um (BSS 40 #) sieve and mixed well. This blend was granulated in planetary mixer using Isopropyl Alcohol. Granules were dried in tray dryer or Fluidized Bed Dryer (FBD) at 50°C. Granules were passed through 1 mm (BSS 16 #) sieve and
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lubricated with Aerosil 200, Magnesium Stearate and Talc and compressed the blend for preparing tablets.
Dissolution was performed as per USP XXIV in 1.0 liter 7.4 pH Phosphate Buffer (0.05M) 100 RPM, at 37°C using apparatus 1. Release profile was as follows:

TIME (HOUR) % DRUG DISSOLVED
1 13.30
2 19.45
4 44.23
6 96.85
Thus Garden cress husk can alone serve the purpose of controlling the release upto eight hours for twice-daily formulation.
Example 6:
Ketorolac Tromethamine is representing a basic molecule with low dose and higher water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm ) according to following formula.

Ingredients Mg/tab Percentage
Ketorolac Tromethamine 30.0 17.17
Garden Cress husk 100.0 57.14
Xanthan gum 10.0 5.71
Dicalcium Phosphate 27.0 15.43
Magnesium stearate 2.0 1.14
Talc 3.0 1.71
Aerosil-200 3.0 1.14
Ketorolac Tromethamine, Garden Cress Husk, Xanthan gum and Dicalcium Phosphate were sifted through 250um (BSS 40 #) sieve and mixed well. This blend was granulated in planetary mixer using Isopropyl Alcohol. Granules were
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dried in Fluidized Bed Dryer (FBD) at 50°C. Granules were passed through 1 mm (BSS 16 #) sieve and lubricated with Aerosil 200, Magnesium Stearate and Talc and compressed the blend for preparing tablets.
Dissolution was performed as per USP XXIV in 0.5 liter 6.8 pH Phosphate Buffer (0.05M) 100 RPM, at 37°C using apparatus 1. Release profile was as follows:

TIME (HOUR) % DRUG DISSOLVED
1 23.98
2 42.62
4 62.58
8 84.27
12 96.42
Example 7:
Tramadol Hydrochloride is representing a acidic molecule with moderate dose and high water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm2 ) according to following formula.

Ingredients Mg/tab Percentage
Tramadol Hydrochloride 100.0 27.39
Garden Cress husk 185.0 50.68
Xanthan gum 18.5 5.07
Dicalcium Phosphate 50.5 13.83
Magnesium stearate 3.0 0.82
Talc 5.0 1.37
Aerosil-200 3.0 0.82
Tramadol Hydrochloride, Garden Cress Husk, Xanthan gum and Dicalcium Phosphate were passed through 250µm (BSS 40# ) sieve and mixed well. This blend was granulated in planetary mixer using Isopropyl Alcohol and dried in Fluidized Bed Dryer (FBD) at 50°C. Granules were passed through 1 mm sieve
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(BSS 16#) and lubricated with Aerosil 200, Magnesium Stearate and Talc and the tablets were compressed.
Dissolution was performed as per USP XXIV in 0.5 liter 6.8 pH Phosphate Buffer (0.05M) 100 RPM, at 37°C using apparatus 1. Release profile was as follows:

TIME (HOUR) % DRUG DISSOLVED
1 28.26
2 41.53
4 60.88
6 75.22
8 86.44
This dissolution profile is meant for twice daily formulation.
Example 8:
Ciprofloxacin is representing a neutral molecule with high dose and low water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm2) according to following formula.

Ingredients mg/tab Percentage
Ciprofloxacin Base 1000.0 75.98
Garden Cress husk 250.0 18.99
Xanthan gum 25.0 1.89
Polyvinylpyrrolidone 90 15.0 1.14
Magnesium stearate 10.0 0.75
Talc 10.0 0.75
Aerosil-200 8.0 0.46
Ciprofloxacin Base, Garden Cress Husk and Xanthan gum were sifted through 250µm (BSS) sieve and mixed well. Polyvinylpyrrolidone 90 was dissolved in Isopropyl Alcohol. The above blend was granulated in planetary mixer using Polyvinylpyrrolidone 90 binder solution. Granules were dried in Fluidized Bed
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Dryer (FBD) at 50°C and passed through 1 mm sieve (BSS 16 #) and lubricated with Aerosil 200, Magnesium Stearate and Talc and compressed the blend for preparing tablets.
Dissolution was performed as per USP XXIV in 1.0 liter, 0.1 N Hydrochloride acid, 100 RPM, at 37°C using apparatus 1. Release profile was as follows:

TIME (HOUR) % DRUG DISSOLVED
1 28.95
2 42.99
4 62.54
6 76.44
Example 9:
Cephalexin is representing an acidic molecule with moderate dose and moderate water solubility. It Tablets were made by compression at usual press (4 to 7 kg/cm ) according to following formula.

Ingredients mg/tab 375.0 Percentage
Cephalexin monohydrate
53.57
Garden Cress husk 250.0 35.71
Xanthan gum 25.0 3.57
Dibasic calcium phosphate 25.0 3.57
Polyvinylpyrrolidone 90 6.0 0.86
Magnesium stearate 5.0 0.71
Talc 6.0 0.86
Aerosil-200 8.0 1.14
Cephalexin monohydrate, Garden Cress Husk and Xanthan gum and Dibasic calcium phosphate were sifted through 250 µm (BSS 40 #) sieve and mix well. Dissolve Polyvinylpyrrolidone 90 dissolved in Isopropyl Alcohol. The above blend was granulated in planetary mixer using Polyvinylpyrrolidone 90 binder
30

solution and dried in Fluidized Bed Dryer (FBD) at 50°C. Granules were passed through 1 mm sieve (BSS 16 #) and lubricated with Aerosil 200, Magnesium Stearate and Talc and compressed the blend for preparing tablets.
Dissolution was performed as per USP XXIV in 1.0 liter, 0.1 N Hydrochloride acid, 100 RPM, at 37°C using apparatus 1. Release profile was as follows:

TIME (HOUR) % DRUG DISSOLVED
1 30.47
2 49.01
4 63.94
8 86.87
Example 10:
Diltiazem hydrochloride is representing an acidic molecule with moderate dose and high water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm2) according to following formula.

Ingredients mg/tab 120.0 Percenta
Diltiazem Hydrochloride
34.28
Garden Cress husk 180.0 51.42
Xanthan gum 18.0 5.14
Dibasic calcium phosphate 15.0 4.28
Polyvinylpyrrolidone 90 5.0 1.42
Magnesium stearate 5.0 1.42
Talc 4.0 1.14
Aerosil-200 3.0 0.32
Diltiazem Hydrochloride, Garden Cress Husk, Xanthan gum and Dibasic calcium phosphate were sifted through 250µm (BSS 40 #) sieve and mixed well. This blend was granulated in planetary mixer using Isopropyl Alcohol and Polyvinylpyrrolidone 90 solution. Granules were dried in Fluidized Bed Dryer
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(FBD) at 50 C and passed through 1 mm (BSS) sieve and lubricated with Aerosil 200, Magnesium Stearate and Talc and compressed the blend for preparing tablets.
Dissolution was performed as per USP XXIV in 1.0 liter 0.1 N Hydrochloric acid at 100 RPM, at 37°C using apparatus 1. Release profile was as follows:

TIME (HOUR) % DRUG DISSOLVED
1 21.71
2 32.85
4 47.69
8 63.94
12 75.12
16 85.89
This formula best describes formulation for once daily administration of Diltiazem Hydrochloride.
Example 11:
Ofloxacin is representing a molecule with moderate dose and moderate water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm ) according to following formula.

Ingredients mg/tab Percentage
Ofloxacin 400.0 62.79
Garden Cress husk 200.0 31.39
Xanthan gum 20.0 3.14
Polyvinylpyrrolidone 90 3.0 0.47
Magnesium stearate 8.0 1.26
Talc 6.0 1.94

Ofloxacin, Garden Cress Husk and Xanthan gum were sifted through 250u.m (BSS 40 #) sieve and mixed well. This blend was granulated in planetary mixer using Isopropyl Alcohol and Polyvinylpyrrolidone 90 solution. Granules were dried in Fluidized Bed Dryer (FBD) at 50°C and passed through 1 mm (BSS) sieve and lubricated with Magnesium Stearate and Talc and compressed the blend for preparing tablets.
Dissolution was performed as per USP XXIV in 1.0 liter 0.1 N Hydrochloric acid at 100 RPM, at 37°C using apparatus 1. Release profile was as follows:

TIME (HOUR) % DRUG DISSOLVED
1 42.21
2 51.43
4 6 65.91 76.66
8 84.61
This formula best describes formulation for once daily administration of Ofloxacin
Example 12:
Nimesulide is representing a molecule with moderate dose and low water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm2) according to following formula.

Ingredients mg/tab 200.00" Percentage
Nimesulide
60.24
Garden Cress husk 80.00 24.01
Polyvinylpyrrolidone 90 3.00 0.90
Magnesium stearate 4.00 1.20
Talc 5.00 1.51
Nimesulide, Garden Cress Husk and Lactose were sifted through 250u.m (BSS 40 #) sieve and mixed well. This blend was granulated in planetary mixer using
33

Isopropyi Alcohol and Polyvinylpyrrolidone 90 solution. Granules were dried in Fluidized Bed Dryer (FBD) at 50°C and passed through 1 mm (BSS) sieve and lubricated with Magnesium Stearate and Talc and compressed the blend for preparing tablets.
Dissolution was performed as per USP XXIV in 1.0 liter 8.0 pH 0.05M phosphate buffer at 100 RPM, at 37°C using apparatus 1. Release profile was as follows:

TIME (HOUR) % DRUG DISSOLVED
1 24.00
2 31.85
4 42.03
8 53.92
This formula best describes formulation for once daily administration of Nimesulide
Example 13:
Cefixime is representing a molecule with moderate dose and very less water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm ) according to following formula.

Ingredients mg/tab Percenta
Cefixime trihydrate 448.00 49.78
equivalent to Cefixime
Garden Cress husk 300.00 33.33
Xanthan gum 30.00 3.33
Colloidal silicon dioxide 6.00 0.67
Magnesium stearate 10.00 1.11
Talc 6.00 0.67
Tabletose 100.00 11.11
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Cefixime, Garden Cress Husk, Xanthan gum, tabletose. Colloidal silicon dioxide , magnesium stearate and talc were sifted through 250µm (BSS 40 #) sieve and mixed well and compressed the blend.
Dissolution was performed as per USP XXIV in 1.0 liter 7.2 pH 0.05M phosphate buffer at 100 RPM, at 37°C using apparatus 1. Release profile was as follows:

TIME (HOUR) % DRUG DISSOLVED
1 17.36
2 22.44
4 30.00
6 8 16 36.04

41.20 60.00
This formula best describes formulation for once daily administration of Cefixime.
Example 14:
Ambroxol Hydrochloride is representing a molecule with low dose and high water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm2) according to following formula.

Ingredients mg/tab Percentage
Ambroxol Hydrochloride 60.00 30.00
Garden Cress husk 90.00 45.00
Xanthan gum 9.00 4.50
Lactose 34.00 17.00
Polyvinyl pyrrolidone 90 2.00 1.00
Magnesium stearate 3.00 1.50
Talc 2.00 1.00


Ambroxol hydrochloride, Garden Cress Husk, xanthan gum and Lactose were sifted through 250µm (BSS 40 #) sieve and mixed well. This blend was granulated in planetary mixer using Isopropvl Alcohol and Polyvinylpyrrolidone 90 solution. Granules were dried in Fluidized Bed Dryer (FBD) at 50°C and passed through 1 mm (BSS) sieve and lubricated with Magnesium Stearate and Talc and compressed the blend for preparing tablets.
Dissolution was performed as per USP XXIV in 0.5 liter 0. 1N hydrochloric acid at 100 RPM, at 37°C using apparatus 1. Release profile was as follows:

Example 15:
Acyclovir is representing a molecule with moderate dose and high water solubility. Tablets were made by compression at usual press (4 to 7 kg/cm2) according to following formula.

Ingredients mg/tab Percentage
Acyclovir 400.00 60.42
Garden Cress husk 200.00 30.21
Xanthan gum 20.00 3.21
Lactose 30.00 4.53
Polyvinyl pyrrolidone 90 5.00 0.75
Magnesium stearate 4.00 0.60
Talc 3.00 0.45


Acyclovir, Garden Cress Husk, xanthan gum and Lactose were sifted through 250um (BSS 40 #) sieve and mixed well. This blend was granulated in planetary mixer using lsopropyl Alcohol and Polyvinylpyrrolidone 90 solution. Granules were dried in Fluidized Bed Dryer (FBD) at 50°C and passed through 1 mm (BSS) sieve and lubricated with Magnesium Stearale and Talc and compressed the blend for preparing tablets.
Dissolution was perfonned as per USP XXIV in 1.0 liter 0. 1N hydrochloric acid at 100 RPM, at 37°C using apparatus 1. Release profile was as follows:

TIME (HOUR) % DRUG DISSOLVED
1 27.69 33.90
2

4 6 43.76
52.15
8 59.34
12 71.87
16 84.15
Example 16 : Bilayer tablet
Bilayered tablet of ciprofloxacin was prepared using this system and dissolution profile was studied.

Ingredients nig/tab Percentage
IR Portion
Ciprofloxacin base 400.00 33.39
Crosscarmelose sodium 10.00 0.83
Magnesium stearate 5.00 0.42
Talc 5.00 0.42
CR Portion
Ciprofloxacin base 600.00 50.08
Garden cress husk 150.00 12.52
Xanthan gum 15.00 1.25
Magnesium stearate 7.00 0.58
Talc 6.00 0.50
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Dissolution was performed as per USP XXIV in 1.0 liter 0. IN hydrochloric acid at 100 RPM, at 37°C using apparatus 1. Release profile was as follows:

TIME (HOUR) % DRUG DISSOLVED
1 54.85
2 66.14
3 78.43
4 90.41
Example 17: Diltiazem hydrochloride pellets

Ingredients mg/tab Percentage
Diltiazem Hydrochloride 120.00 33.52
Garden Cress husk 200.00 55.86
Xanthan gum 18.00 5.02
Dibasic calcium phosphate 15.00 4.19
Polyvinylpyrrolidone 90 5.00 1.39
Diltiazem hydrochloride, garden cress husk, xanthan gum, dibasic calcium phosphate and polyvinylpyrrolidone 90 were sifted through 250µm (BSS 40 #) sieve and mixed well. This blend was spheronized in spheronizer to obtain pellets.
38
Dissolution was performed as per USP XXIV in 1.0 liter 0.1 N Hydrochloric acid at 100 RPM, at 37°C using apparatus 1. Release profile was as follows:


Various examples as mentioned above proves conclusively beyond doubt the suitability of polymer with marked difference in their physicochemical properties. This uniqueness qualifies it to be used as platform technology for oral administration of therapeutic agent or drug.
39

CLAIMS
1. A solid controlled release oral unit dose pharmaceutical composition, comprising one or more of therapeutic agent/drug and a gel forming husk powder obtained from Lepidium sativum seeds.
2. A composition according to claim 1, further comprising one or more cross-linking enhancers.
3. A composition according to any one of claims 1 or 2, further comprising one or more pharmaceutically acceptable excipients.
4. A composition according to claim 2 wherein the gel forming husk powder obtained from Lepidium sativum seeds is present in the range of 10 to 70 % of the total weight of dosage form, the cross-linking enhancer selected from xanthan gum, karaya gum, cellulose ethers like methyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose and their salts, alginates, polyvinyl alcohols and ethyl cellulose or a combination thereof in amounts of between 3 to 10% by weight of the dosage form to give a release profile between 4 to 20 hours.
5. A composition according claim 1 wherein the therapeutic agent/drug consists of an acidic, basic and neutral drug selected from the group are analgesics, anti¬inflammatory agents, anthelmintics, anti-arrhythmic agent, anti-asthma agent, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti¬diabetics, anti-epileptics, anti-fungal agents, anti-gout agent, anti-hypertensive agents, anti-malarials, anti-migraine agent, anti-muscarinic agents, anti-neoplastic agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anti-
40

tussives. bronchodilators, anxiolytic, sedatives, hypnotics, neuroleptics, beta -Blockers, cardiac inotropic agents, corticosteriods, diuretics, antiparkinsonian agent, gastro-intestinal agents, histamine H, -receptor antagonists, keratolytics, lipid regulating agent, muscle relaxants, anti-anginal agents, nutritional agents. NSAID's, sex hormones, stimulants, cytokines, peptidomimetics, antibacterial / anti-infective agents and mixtures thereof.
6. A composition according claim 3 wherein the total excipients present is between 10 to 40 % by weight of the total dosage form.
7. A composition according claim 2 wherein the cross-linking enhancer is xanthan gum being present in amounts of from 3 to 10 % by weight of the dosage form.
8. A method for production of solid controlled release oral unit dose pharmaceutical composition, which comprises blending one or more therapeutic agent/drug and a gel forming husk powder obtained from Lepidium sativum seeds.
9. A method according to claim 8, wherein one or more cross-linking enhancers are added.
10. A method according to claims 8 or 9, wherein one or more pharmaceutically acceptable excipients are added.
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1 l.A method according to claim 8 wherein the gel formiing husk powder obtained from Lepidium sativum seeds is added in an amount of from 10 to 60 % of the total weight of dosage form.
12. A method according to claim 9 wherein the cross-linking enhancer is selected from xanthan gum, karaya gum, cellulose ethers like methyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose and their salts, alginates, polyvinyl alcohols and ethyl cellulose or a combination thereof is added in an amount of from 3 to 10% by weight of the dosage form to give a release profile between 4 to 20 hours.
13. A method according to claim 8 wherein, therapeutic agent/drug consists of an acidic, basic and neutral drugs selected from the group are analgesics, anti¬inflammatory agents, anthelmintics, anti-arrhythmic agent, anti-asthma agent, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti¬diabetics, anti-epileptics, anti-fungal agents, anti-gout agent, anti-hypertensive agents, anti-malarials, anti-migraine agent, anti-muscarinic agents, anti-neoplastic agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anti¬tussives, bronchodilators, anxiolytic, sedatives, hypnotics, neuroleptics, beta -Blockers, cardiac inotropic agents, corticosteriods, diuretics, anti-parkinsonian agent, gastro-intestinal agents, histamine H, -receptor antagonists, keratolytics, lipid regulating agent, muscle relaxants, anti-anginal agents, nutritional agents, NSAID's, sex hormones, stimulants, cytokines, peptidomimetics, antibacterial / anti-infective agents and mixtures thereof and also their pharmaceutically acceptable salt.
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14. A method according to claim 9 wherein, the total excipients may be between 10 to 40 % by weight of the total dosage form.
15.A method according to claim 8 where the composition is made in the form of tablets, capsules and pallets.
Dated this 4th day of June 2002.

S. MAJUMDAR of S. MAJUMDAR & CO. Applicants' Agent
43