FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)

TITLE OF THE INVENTION

"SPECIALIZED CONTROLLED RELEASE ORAL DOSAGE FORMS

FOR pH DEPENDENT SOLUBILITY ACTIVE INGREDIENTS"

We, TORRENT PHARMACEUTICALS LIMITED, Off Ashram Road, Near Dinesh Hall, Ahmedabad 380 009, Gujarat, India.

The following specification describes the invention:

Specialized Controlled Release Oral Dosage Forms for pH dependent Solubility Active Ingredients
Field of Invention
The invention relates to specialized controlled release oral dosage form(s) for pH dependent solubility active ingredients, which reduce the effect of different pH of various portions of gastrointestinal tract on drug release from the dosage form wherein the active ingredient does not have absorption window in the proximal part of the intestine. This invention further relates to a process for preparing the dosage form(s).
Background of the invention
During the past three decades significant advances have been made in the area of controlled drug delivery. This was, in part, due to the evolving disciplines of biopharmaceutics, pharmacokinetics and pharmacodynamics. In a typical therapeutic regimen, the drug dose and the dosing interval are optimized to maintain drug concentration within the therapeutic window, thus ensuring efficacy while minimizing toxic side effects. Surveys indicated that dosing more than once or twice daily greatly reduces patient compliance. Hence, the primary objective for controlled drug delivery is to maintain drug concentration within therapeutic window, improve patient compliance to the dosage regimen by decreasing dosing frequency, and improve drug efficacy while reducing toxic side effects. Proper control of drug release from the controlled release dosage form is very important to get desired efficacy. For most of the active ingredients a pH independent release of active ingredient from the dosage form is ideal. This type of release profile is achievable by using the conventional controlled release dosage forms for the drugs having solubility that is fairly same at the physiological pH range of gastrointestinal tract. In cases where the solubility of the active ingredient is significantly different at different pH special dosage forms like osmotic pumps are used to obtain pH independent drug release. Manufacturing of such dosage forms require special equipments like laser drilling which are very expensive and involve highly skilled and precise operations.
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Human Gastrointestinal tract has wide pH range at different portions of it, which ranges from pH 1 to pH 8. There are many active ingredients whose solubility is significantly different at this pH range. Moreover the motility of gastrointestinal tract varies with individual and within individual resulting in variability in dosage form residence time in the different portions of gastrointestinal tract. This gives rise to different drug release profile of an active ingredient having pH dependent solubility. Ultimately it results in variation in drug plasma concentration and might affect the efficacy.
This necessitates the need to develop specialized controlled release oral dosage form(s) for pH dependent solubility active ingredients, which reduce the effect of different pH of various portions of gastrointestinal tract on drug release from the dosage form(s) wherein the active ingredient does not have absorption window in the proximal part of the intestine. This invention further relates to a process for preparing the dosage form.
Prior Art
There are numerous patents on dosage forms based on osmotic principle, which provide pH independent drug release. Manufacturing of such dosage forms require special equipments like laser drilling which are very expensive and involve highly skilled and precise operations.

US Patent number Details of Patent
3,845,7703,916,8994,008,7194,036,2274,088,864 4,111,2014,256,108 First general patent describing osmotic pump and list of polymers for semipermeable membrane along with their WVTR Continuation of patent number 3,845,770 gives calculation of the optimum diameter of the passage way including Amax and Amin Use of two adjacent semipermeable coatings of different composition in osmotic pumps. Delaying drug release by using bioerodible outer coatingDetails of laser drilling in osmotic pumps. Osmotic pump containing expandable mini pumps which control release of drug. Use of two adjacent membranes (semipermeable and microporous), a list of |dispersants is given
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US Patent number
4,271,113 4,326,525
4,344,929
4,309,996
4,327,725 4,522,625 4,612,008 4,751,071 4,992,278
5,082,668 5,208,037
5,232,705
5,221,536 5,252,338

Details of Patent
Automatic orifice formation during coating
due to recess in core tablet
Improved drug delivery properties by use of
buffer compounds to moderate drug
solubility
Use of effervescent activity to prevent
blocking of orifice due to preciptation of
drug in acidic environment.
Bicompartment osmotic pump contains a
swellable osmopolymer forming expandable
chamber.
Bilayered osmotic device with hydrogel as
driving member
Semipermeable membrane blended with enteric
coatings.
Osmotic pump of diclofenac sodium with dual
thermodynamic activity.
Zero order delivery of drugs joined with
pulsed release of drugs.
Delivery of poorly water soluble drug in
the suspension form (using a swelling
agent) from single layer osmotic pump.
Calculation for bilayered osmotic devices.
Use of different molecular weight sodium
carboxymethylecellulose in different
compartment
Device for time varying patterns of drug
delivery like providing drug free interval,
pulsated drug delivery
Bilayered osmotic pump for antiparkinsonism
drugs.
Push pull osmotic pump for delayed drug
release (after administration initially a
drug free period).

There are number of dosage forms which are described in many patents which are designed to be retained in the stomach for extended period of time for the active ingredients which have absorption window in the proximal part of the intestine. Few of such patents are as follows-
S. Watanabe et al, U.S. Pat. No. 3,976,764 teach the use of a hollow or low density core surrounded by polymeric materials containing drug(s). The device floats in the stomach and releases said drug over an extended period of
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time.
Sheth and Tossounian, U.S. Pat. Nos. 4,140,755 and
4,167,558 describe the use of a tablet which is
hydrodynamically balanced to be buoyant under gastric
conditions thereby remaining in the stomach for an extended
period of time.
Mamajek and Moyer, U.S. Pat. No. 4,207,890 teach the use of an expandable envelope containing a drug and an agent which expands when gastric fluid permeates through the envelope.
Theeuwes and Urquhart, U.S. Pat. No. 4,434,153 describe the use of a device (containing a hydrogel) which can enter intb the gastrointestinal environment where it imbibes fluid and swells 2-50 fold so that it is retained in the stomach over an extended period.
Alza Corporation, U.S. Pat. Nos. 3,797,492 and 3,901,232 disclose the use of inflatable bags containing a gas or vapor-generating system to cause inflation following release of the device from a bioerodible capsule in the stomach .(or other desired body cavity). The inflated envelope causes the device to be retained in the desired site (e.g. stomach) and drug is released from an attached delivery system.
These patents do not teach about dosage forms for pH dependent solubility active ingredients, which reduce the effect of different pH of various portions of gastrointestinal tract on drug release from the dosage form.
Detailed Description of the Invention
Controlled release refers to the release of an agent such as a drug from a composition or dosage form in which the agent is released according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow delivery of an agent to a subject over an extended period of time according to predetermined profile. Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic or diagnostic response as compared to conventional rapid release dosage forms. Such longer
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periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations. For example, in the treatment of chronic pain, controlled release formulations are often highly preferred over conventional short-acting formulations.
Controlled release pharmaceutical compositions and dosage forms are designed to improve the delivery profile of agents, such as drugs, medicaments, active agents, diagnostic agents, or any substance to be internally administered to an animal, including humans. A controlled release composition is typically used to improve the effects of administered substances by optimizing the kinetics of delivery, thereby increasing bio-availability, convenience, and patient compliance, as well as minimizing side effects associated with inappropriate immediate release rates such as a high initial release rate and, if undesired, uneven blood or tissue levels.
pH dependent solubility of the active ingredient here refers to solubility of active ingredient in mg/ml which is different by at least 20% at pH of 1.2 and 6.8 at 37°C. For example if solubility of active ingredient 'X' is 1 mg/ml at pH 1.2 (0.1N HC1) then at pH 6.8 it should be either below 0.8 mg/ml or above 1.2 mg/ml. The solubility of active ingredient is determined by standard method of finding solubility.
Here 'initial portion of gastrointestinal tract' refers to oral cavity, esophagus and stomach.
The term "proximal part of gastrointestinal tract" as used herein refers to stomach, duodenum, jejunum and ileum.
The term "release controlling agents" as used herein refers to polymer based or non-polymer based material, which help to modify the release of active ingredient present in the dosage form as per the present invention.
The term "non-biodegradable materials" as used herein refers to materials (polymers or non-polymers) which do not dissolve or degrade or metabolized in the fluids of gastrointestinal tract of mammals.
The term "inlay- tablet" as used herein refers to a variation of the compression-coated tablet, also referred to as a dot, or bull's-eye tablet. Instead of an inner core zone being completely surrounded by an outer coat, one surface of the zone corresponding to an inner core zone is exposed.
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The invention provides specialized controlled release oral dosage form(s) for pH dependent solubility active ingredients, which reduce the effect of different pH of various portions of gastrointestinal tract on drug release from the dosage form wherein the active ingredient does not have absorption window in the proximal part of the intestine and process of preparing the dosage, form(s).
These specialized dosage forms are designed for releasing majority of the pH dependent solubility active ingredient present in the dosage form as per the instant invention at initial portion of the gastrointestinal tract.
One category of specialized dosage forms as per the instant invention are controlled release dosage forms comprising pH dependent solubility active ingredient(s), which swell or float in the contents of stomach and remain there for extended period of time. These are matrix-based tablets which comprise hydrophilic swellable release controlling agent(s) and optionally comprise gas-generating agents. These tablets may be optionally coated with functional or non-functional coating and/or may be multilared.
Another category of specialized dosage forms as per the instant invention are controlled release dosage forms comprising pH dependent solubility active ingredient (s), which do not swell or float in the contents of stomach and but remain there for extended period of time due to their size. These are matrix-based tablets comprising nonbiodegradable material(s). These tablets may be optionally coated with functional or non-functional coating and/or may be multilared.
Yet another category of specialized dosage forms as per the instant invention are controlled release dosage forms comprising pH dependent solubility active ingredient(s) and mucoadhesive release controlling agents. These dosage forms adhere to the mucus of the initial portion of the gastrointestinal tract and remains there for extended period of time. These dosage forms are in the form of pellets, microspheres, microcapsules, soft gelatin capsule, hard gelatin capsule, flakes, liposomes, nanoparticles, sheets or tablets.
Another object of the present invention is to prepare controlled release dosage forms comprising pH dependent solubility active ingredient(s)in the form of an inlay tablet.
The pH dependent solubility active ingredient (s) can be present in the form of a free base or in the form of
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pharmaceutical!]/ acceptable salts. Pharmaceutical!;/ acceptable salts forming part of this invention are intended to define but not limited to salts of the carboxylic acid moiety such as alkali metal salts like Li, Na and K salts; alkaline earth metal salts like Ca and Mg salts; salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline, and the like; ammonium or substituted ammonium salts and aluminium salts. Salts may be acid addition salts which defines but not limited to sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzensulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
Further, the pH dependent solubility active ingredient(s) , where applicable, may be present either in the form of one substantially optically pure enantiomer or as a mixture of enantiomers or polymorphs thereof.
The pH dependent solubility active ingredient(s) are comprises of the following therapeutic classes but not limited to antidiabetic agents, anti-histamines, antipyretics, anti-depressants, anti-viral agents, anesthetics, antacids, anti-arththriics, antibiotics, anti-psychotics, anti-spasmodics, anxiolytic agents, appetite suppressants, cardiovascular agents, cough suppressants, emollients, gastro-intestinal agents, growth regulators, respiratory stimulants, vitamins, angiotensin converting enzyme inhibitors, anti-asthmatics, anti-cholesterolemics, anticonvulsants, anti-depressants, anti-diarrhea preparations, anti-infective, anti-inflammatory agents, anti-nauseants, anti-stroke agents, anti-tumor drugs, anti-tussives, anti-uricemic drugs, amino-acid preparations, antiemetics, antiobesity drugs, antiparasitics, antipyretics, appetite stimulants, cerebral dilators, chelating agents, cholecystokinin antagonists, cognition activators, deodorants, dermatological agents, diuretics, erythropoietic drugs, fertility agents, synthetic hormones, laxatives, mineral supplements, neuroleptics, neuromuscular agents, peripheral vaso-dilators, prostaglandins, vaginal preparations, vaso-constrictors, vertigo agents, sulphonylurease, meglitinides, PPAR gamma agonist [insulin sensitisers (thiazolidinedione)], PPAR alpha and gamma agonist, alpha-glucosidase inhibitors.
One example of pH dependent solubility antiepileptic active ingredient is lamotrigine.
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The particle size and surface area of the pH dependent solubility active ingredient(s) can be selected based on the solubility, permeability, dose and type of the dosage form.
Strength of pH dependent solubility active ingredient(s) per unit dosage form may vary from 0.1 mg to 1000 mg.
The specialized controlled release dosage form(s) as per the instant invention comprise at least one release controlling agent and other pharmaceutically acceptable excipient (s) . These pharmaceutically acceptable excipients are selected from the following categories but not limited to diluent, adsorbent, antioxidant, buffering agent, colorant, flavorant, sweetening agent, antiadherent, binder, direct compression excipient, disintegrant, glidant, lubricant, opaquant and/or polishing agents.
The amount of release controlling agent (s) to be used in will be determined based on drug release rate etc.
The release controlling agents(s) are selected from alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic acids and esters thereof, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene terephthalates, polyvinyl esters, polyvinylpyrrolidone, polyglycolides, polysiloxanes and polyurethanes and co-polymers thereof.
The high water soluble/permeable release controlling agents
is suitably polyvinyl alcohol, polyvinylpyrrolidone,
methylcellulose, hydroxypropylcellulose,
hydroxypropylmethyl cellulose or polyethylene glycol, alginates, polyacrylic acids, xanthun gum or a mixture thereof.
The low water soluble/permeable release controlling agents is suitably ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), and poly (hexyl methacrylate). Poly(isodecyl methacrylate), poly (lauryl methacrylate), poly(phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl actylate), poly (octadecyl acrylate), waxes such as beeswax, carnauba wax, microcrystalline wax, and ozokerite; fatty alcohols such as cetostearyl alcohol, stearyl alcohol; cetyl alcohol and myristyl alcohol; and fatty acid esters such as glyceryl monostearate, glyceryl
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distearate, glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, and hydrogenated castor oil or a mixture thereof.
The non-biodegradable materials are selected from but are not limited to Ammonio methacrylate copolymers type A and B as described in USP, Polyacrylate dispersion 30% as described in Ph. Eur., Polyvinyl acetate dispersion, cellulose derivatives such as ethylcellulose, cellulose acetate waxes such as beeswax, carnauba wax, microcrystalline wax, and ozokerite; fatty alcohols such as cetostearyl alcohol, stearyl alcohol; cetyl alcohol and myristyl alcohol; and fatty acid esters such as glyceryl monostearate, glyceryl distearate, glycerol monooleate,, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, and hydrogenated castor oil.
The mucoadhesive release controlling agents are selected from but are not limited to carbopol, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium hyaluronate, gaur gum, sodium alginate, polycabophil, starch, dextran or chitosan.
As used herein, the term “diluent" is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets. Such compounds include, by way of example and without limitation, Carbohydrates including sugars and polysaccharides and their derivatives, inorganic salts, organic salts. Example of soluble diluents belonging to above classes are but not limited to glactose, sucrose, mannitol, sorbitol, fructose, maltose, lactose, sodium chloride, potassium chloride, stach, microcrystalline cellulose, dicalcium phosphate and other materials known to one of ordinary skill in the art.
As used herein, the term wadsorbent" is intended to mean an agent capable of holding other molecules onto its surface by physical or chemical (chemisorption) means. Such compounds, include, by way of example and without limitation, powdered and activated charcoal and other materials known to one of ordinary skill in the art.
As used herein, the term * antioxidant" is intended to mean an agent, which inhibits oxidation and thus is used to prevent the deterioration of preparations by the oxidative process. Such compounds include, by way of example and
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without limitation, ascorbic acid, ascorbyl palmitate, butylated hydroxynisole, butylated hydroxytoluence, hypophophorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate and sodium metabisulfite and other materials known to one of ordinary skill in the art.
As used herein, the term "buffering agent" is intended to mean a compound used to resist change in pH upon dilution or addition of acid or alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dyhydrate and other materials and other materials known to one or ordinary skill in the art.
As used herein, the term "antiadherents" is intended to mean agents which prevent the sticking of tablet formulation ingredients to punches and dies in a tableting machine during production. Such compounds include by way of example and without limitation, magnesium stearate, talc, calcium stearate, glyceryl behenate, PEG, hydrogenated vegetable oil, mineral oil, stearic acid and other materials known to one or ordinary skill in the art.
As used herein, the term "binders" is intended to mean
substances used to cause adhesion of powder particles in
tablet granulations. Such compounds include, by way of
example and without limitation, acacia, alginic acid,
carboxymethylcaellulose sodium,
poly(vinylpyrrolidone),compressible sugar (e.g. NuTab), ethylcellulose, gelatin, liquid gluclose, methylcellulose, povidone and pregelatinized starch and other materials known to one of ordinary skill in the art.
When needed, binders may also be included in the tablets. Exemplary binders include acacia, tragacanth, gelatin, starch, cellulose materials such as methyl cellulose and sodium carboxy methyl cellulose, alginic acids and salts thereof, polyethylene glycol, sugar gum,- polysaccharide, bentonites, sugars, invert sugars, polyoxamers (PLURONIC F68, PLURONIC F 127), collagen, albumin, gelatin, cellulosics in non-aqueous solvents, combinations thereof and the like. Other binders include, for example, polypropylene glycol, polyoxyethelene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, combination thereof and other materials known to one of ordinary skill in the art.
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As used herein, the term * direct compression excipient" is intended to mean a compound used in direct compression tablet formulations. Such compounds include, by way of exampled and without limitation, dibasic calcium phosphate (e.g. Ditab) and other materials known to one of ordinary skill in the art.
As used herein, the term "glidant" is intended to mean agents used in tablet and capsule formulations to reduce friction during tablet compression. Such compounds include, by way of example and without limitation, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, colloidal silicon, silicon hydrogel and other materials known to one of ordinary skill in the art.
As, used herein, the term * lubricant" is intended to mean substances used in tablet formulations is reduce friction during tablet compression. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc Stearate and other materials known to one of ordinary skill in the art.
As used herein, the term "opaquant" is intended to mean a compound used to render a capsule or a tablet coating opaque. May be used along or in combination with a colorant. Such compounds include, by way of example and without limitation, titanium dioxide and other materials known to one of ordinary skill in the art.
As used herein, the term "polishing agent" is intended to mean a compound used to impart an attractive sheet to coated tablets. Such compounds include, by way of example and without limitation, carnauba wax, and white wax and other materials known to one or ordinary skill in the art.
As used herein, the term “disintegrant" is intended to mean a compound used in solid dosage forms to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as benotonite, microcrystalline cellulose (e.g. Avicel). carboxymethylcellulose calcium, cellulose polyacrilin potassium (e.g. Amberlite) , alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth and other materials known to one of ordinary skill in the art.
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As used herein, the term * colorant" is intended to- mean a compound used to impart color to solid (e.g. tablets) pharmaceutical preparations. Such compounds include, by way of example and without limitation, FD&C Red No.3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and ferric oxide, red, other F.D & C dyes and natural colouring agents such as grape skin extract, beet red powder, beta-carotene, annatto, carmine, turmeric, paprika and other materials known to one or ordinary skill in the art. The amount of coloring agent used will vary as desired.
As used herein, the term "'f lavorant" is intended to mean a compound used in impart a pleasant flavor and often odor to a pharmaceutical preparation. Exemplary flavoring agents or flavorants include synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof. These may also include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, ceder leave oil, oil of nutmeg , oil of sage, oil of bitter almonds and cassia oil. Other useful flavors include vannila, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. Flavors that have been found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavours and mixtures thereof. The amount of flavoring may depend on a number of factors, including the organoleptic effect desired. Flavors will be present in any amount as desired b those of ordinary skill in the art. Particularly preferred flavours are the grape and cherry flavors and citrus flavors such as orange.
The present tablets can also employ one or more commonly known surface active agents or cosolvents that improve wetting or disintegration of the tablet core or layers.
Plasticizers can also be included in the tablets to modify the properties and'characteristics of the polymers used in the coats or core of the tablets. As used herein, the term
‘plasticizer' includes, all the compounds capable of plasticizing of softening of polymer or binder used in invention. The plasticizer should be able to lower the melting temperature or glass transition temperature
(softening point temperature) of the polymer or binder. Plasticizers, such as low molecular weight PEG, generally broaden the average molecular weight of a polymer in which
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they are included thereby lowering its glass ' transition temperature or softening point. Plasticizers also generally reduce the viscosity of a polymer.
Plasticizers useful in the invention can include, by way of example and without limitation, low molecular weight polymers, oligomers, copolymer-s, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, single block polymers, low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol and glycerin. Such plasticizers can also include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol, monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutylsebacate, acetylributycitrate, triethyl citrate, acetyl triethyl citrate, tributyl citrate and allyl glycolate. All such plasticizers are commercially available from sources such as Aldrich or Sigma Chemical Co. It is also contemplated and within the scope of the invention, that a combination of plasticizers may be used in the present formulation. The PEG based plasticizers are available commercially or can be made by a variety of methods such as disclosed in Poly(ethylene glycol) Chemistry : Biotechnical and Biomedical Applications (J.M. Harris, ed. : Plenum Press, NY) the disclosure of which is hereby incorporated by reference.
Soaps and synthetic detergents may be employed as surfactants and as vehicles for detergent compositions. Suitable soaps include fatty acid alkali metal, ammonium and triethanolamine salts. Suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; anionic detergents, for example, alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates, and poly(oxyethylene)-block-poly(oxypropylene) copolymers; and amphoteric detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene) -block-poly(oxypropylene) copolymers; and amphoteric detergents, for example, alkyl P-aminopropionates and 2-alkylimidazoline quaternary ammonium salts; and mixtures thereof various other components, not
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otherwise listed above, can be added to the present
formulation for optimization of a desired active agent
release profile including, by way of example and without
limitation, glycerylmonistearate, nylon, cellulose acetate
butyrate,d,1-poly(lactic acid) , 1, 6-hexanediamine,
diethylenetriamine, starches, derivatized starches, acetylated monoglycerides, gelatin coacervates, poly(styrene-maleic acid) copolymer, glycowax, castor wax, stearyl alcohol, glycerol palmitostearate, poly-(ethylene) , poly (vinyl acetate), poly (vinyl chloride), 1,3-butylene-glycoldimethacrylate, ethyleneglycol-dimethacrylate and methacrylate hydrogels.
The granules of the tablet and capsule dosage forms can be manufactured in accordance with usual granulation techniques in which the active ingredient and other excipients are mixed and granulated by adding solution of binder in a low or high shear mixer or by fluidized bed granulation. The granulate is dried, preferably in a fluidized bed dryer. The dried granulate is sieved and mixed with other excipients. Alternatively the manufacture of granules of matrix formulation can be made by direct mixing of the directly compressible excipients or by roller compaction. The granules can be compressed into single layered tablets, multilayered tablets or inlay tablets.
Pellets can be manufactured by spheronization, powder layering, solution layering, agitation, melt granulation, or spray drying.
Liposomes can be oligolamellar, unilamellar or multilamellar vesicles and can be manufactured by various methods like dehydration or rehydration, removal of lipid solubilization agent or reverse phase evaporation.
Nanoparticles can be manufactured by various methods like insitu polymerization, emulsification polymerization or dispersion polymerization.
Microspheres and microcapsules can be manufactured by various methods like spray drying, fluid bed coating, phase separation, solvent evaporation, solvent extraction or cryogenic solvent extraction.
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Soft gelatin capsule can be manufactured by various methods like plate process, rotary die process, accogel process or bubble method.

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Abstract
Specialized controlled release oral dosage form(s) for pH dependent solubility active ingredients, which reduce the effect of different pH of various portions of gastrointestinal tract on drug release from the dosage form, wherein the active ingredient does not have absorption window in the proximal part of the intestine and process of preparing the dosage form(s).
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